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Priority Medicines for Europe and the World
"A Public Health Approach to Innovation"
Update on 2004 Background Paper
Background Paper 6.23
Neonatal Conditions
By Clara Setiawan, MPH, BSc
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-2
Table of Contents
Glossary ................................................................................................................................................. 3
Executive Summary ............................................................................................................................. 4
1. Introduction .................................................................................................................................. 5
1.1 Background ........................................................................................................................... 5
1.1.1 Premature Birth................................................................................................................. 6
1.1.2 Neonatal Infections .......................................................................................................... 7
1.1.3 Birth Asphyxia .................................................................................................................. 7
1.2 Neonatal Conditions: Burden of Disease .......................................................................... 8
1.3 Global Burden of Disease .......................................................................................................... 8
1.4 EU/EEA Burden of Disease ............................................................................................... 11
1.4.1 Preterm birth ................................................................................................................... 12
1.4.2 Sepsis ................................................................................................................................ 13
1.4.3 Encephalopathy .............................................................................................................. 14
2. Control Strategy ......................................................................................................................... 15
2.1 Vaccination .......................................................................................................................... 15
2.2 Other Preventative Approaches ....................................................................................... 16
2.2.1 Preterm birth ................................................................................................................... 16
2.2.2 Sepsis ................................................................................................................................ 17
2.3 Diagnostic Testing .............................................................................................................. 18
2.3.1 Sepsis ................................................................................................................................ 18
2.4 Treatment ............................................................................................................................. 19
2.4.1 Preterm birth ................................................................................................................... 19
2.4.2 Sepsis ................................................................................................................................ 24
2.4.3 Birth Asphyxia ................................................................................................................ 28
3. Research and Development ..................................................................................................... 31
3.1 Pharmaceuticals .................................................................................................................. 31
3.1.1 Preterm ............................................................................................................................. 31
3.1.2 Sepsis ................................................................................................................................ 32
3.1.3 Birth Asphyxia ................................................................................................................ 32
3.2 Diagnostics .......................................................................................................................... 33
3.2.1 Sepsis ................................................................................................................................ 33
3.3 EC Framework Programme .............................................................................................. 33
4. Existing Resource Flows ........................................................................................................... 35
4.1 Finance for Research and Development .......................................................................... 35
5. Challenges and Research Opportunities .............................................................................. 36
6. Conclusions ................................................................................................................................ 37
References ........................................................................................................................................... 38
Annex ................................................................................................................................................... 47
Annex 6.23.1: The reimbursed price for animal derived surfactants in European countries
in 2012 .............................................................................................................................................. 47
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-3
Glossary
Terms and acronyms Definitions
CI Confidence interval
COX Cyclo-oxygenase
DALYs Disability-adjusted life years
EU European Union
IgG Immunoglobulin
LOC Lab-on-a-chip
MDG Millennium Development Goal
MNCH Maternal, newborn, and child health
NMR Neonatal mortality rate (per 1 000 livebirths)
PA Progestational agents
PCR Polymerase chain reaction
pPROM Premature rupture of membranes
RDS Respiratory distress syndrome
RR Relative risk
STI Sexually transmitted infection
Tx Treatment
WHO World Health Organization
YLD Years lived with disability
YLL Years of life lost
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-4
Executive Summary
The neonatal period is only the first 28 days of life and yet accounts for 40% of all deaths in
children under-five. Globally, neonatal conditions accounted for 3 072 000 deaths in 2010
alone. Although the number of neonatal deaths has decreased since 1990, all regions have
seen slower reductions in neonatal mortality compared to under-five mortality resulting in
an increased share of neonatal deaths among total under-five deaths. In order to achieve the
Millennium Development Goal 4 in reducing the under-five mortality rate by two-thirds by
2015, neonatal conditions need to be addressed immediately.
Among many neonatal conditions; 1) premature birth, 2) neonatal infections, and 3) birth
asphyxia, were identified as major contributors to the global burden of disease. Due to the
complex etiology of these conditions, preventive methods, diagnostic tools, and treatments
remain limited. Many of the current preventive approaches focus on maternal health prior to
the newborn’s arrival such as maternal immunization and ensuring a healthy pregnancy.
Several treatments exist for neonatal conditions that may reduce the risk of maternal and
neonatal mortality. However, these treatments are still not ideal in formulation, packaging,
and/or accessibility. For example, several tocolytics are available to inhibit preterm labor, but
are often accompanied by adverse side effects to both the mother and newborn. The current
formulation and packaging for the recommended antibiotics to treat neonatal sepsis are not
readily available and require properly trained care providers to administer them. Surfactant
preparations are effective in treatment of newborns with respiratory distress syndrome, but
are expensive to produce and are limited. Furthermore, lack of rapid diagnostics often leads
to non-judicial use of antibiotics that may contribute to the rising concern for antimicrobial
resistance. These are only several challenges that currently exist in addressing neonatal
conditions.
Despite the large global burden from neonatal conditions, investment in research funding for
neonatal survival is extremely low. It is estimated that only around US$ 20 million per year is
invested into research for neonatal survival. A recent global analysis suggests that newborn
survival will remain vulnerable on the global agenda without adequate funding and without
high-level engagement of policy-makers. For this reason it becomes imperative that more
funding and long-term support from the European Commission be allocated towards
research and development addressing neonatal conditions.
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-5
1. Introduction
In 2004, a report, Priority Medicines for Europe and the World, was written by Warren Kaplan
and Richard Laing and published by the World Health Organization (WHO). The topic and
background paper on neonatal conditions was not included in the 2004 report.
As a result of the 2008 updated Global Burden of Disease list released by the WHO and the
2010 Global Burden of Disease study published by the Lancet, neonatal conditions are now
included in this report.1,2 Related to the rising need for attention to neonatal conditions, other
important reports such as Born Too Soon: The Global Action Report on Preterm Birth was
published in 2012 in support of the Global Strategy for Women’s and Children’s Health and
the efforts of the Every Woman Every Child campaign, led by the UN Secretary-General, Ban
Ki-moon.3
In this paper, you will find the background on neonatal conditions including its disease
burden, both globally and in Europe; the current control strategies via vaccinations,
preventative approaches, and treatments; current research and development activities
including the lessons learned from past research and the current pipeline. Most importantly,
this paper will expose the pharmaceutical gaps that needs to be addressed and highlight
opportunistic areas for research and development. This background paper will serve as the
basis for the chapter to be found in the updated 2013 Priority Medicines report.
1.1 Background
Neonatal conditions are defined as conditions occurring during the first month after birth (0-
28 days). Among many neonatal conditions; 1) premature birth, 2) neonatal infections, and 3)
birth asphyxia, were identified as major contributors to the global burden of disease and will
be the conditions focused on in this chapter.1,2
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-6
Figure 6.23.1: Global causes of childhood deaths in 2010
Source: Global, regional, and national causes of child mortality: an updated systematic analysis for
2010 with time trends since 2000. Liu et al. The Lancet (May 11, 2012) 4
1.1.1 Premature Birth
Premature birth is defined by the WHO as all births before 37 completed weeks of gestation
or fewer than 259 days since the first day of a woman’s last menstrual period.3 Causes of
premature births are typically classified into two subtypes: 1) spontaneous preterm birth
(spontaneous onset of labor or following pre-labor premature rupture of membranes
(pPROM)) and 2) provider-initiated preterm birth (induction of labor or elective caesarian
birth for maternal or fetal indications or other non-medical reasons).3 Risk factors for
spontaneous preterm birth has been identified such as age, multiple pregnancy, infection,
maternal medical conditions and psychological health, nutritional, lifestyle, and genetic
factors.3
Complications of premature birth are the single largest contributor to neonatal mortality. In
addition to mortality outcomes, the implications of being born too soon extend beyond the
neonatal period. Preterm babies lack the necessary physical development which often
requires special care and they face greater risks of serious health problems in the future.3
Survivors of premature birth may suffer lifelong effects such as impaired
neurodevelopmental functioning, higher risk of non-communicable disease, and physical
impairments in visual, hearing, lung function, and cardiovascular function.3,5
n = 7.6 million
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-7
1.1.2 Neonatal Infections
The term “neonatal infections” in this background paper includes all infections except for
diarrhoeal diseases and neonatal tetanus. Among the infections, sepsis and pneumonia
account for the majority of the burden.6 Neonatal pneumonia will be discussed in detail in
Background Paper 6.22, while neonatal sepsis will be the focus of neonatal infections in this
chapter.
Neonatal sepsis is a blood infection that can be caused by a number of different bacteria,
including Escherichia coli (E. coli), Listeria, and certain strains of Streptococcus.7 Streptococcus
agalactiae (Group B Streptococcus, GBS) is the most common cause of neonatal sepsis in many
countries, though lower rates are reported from many low-income countries particularly in
South Asia.8
Early-onset neonatal sepsis is seen within the first seven days of life and most often appears
within 24 hours of birth where the baby is infected from the mother before or during the
delivery.7 Preterm delivery, rupture of membranes longer than 24 hours before birth,
infection of the placental tissue and amniotic fluid (chorioamnionitis), and group B
Streptococcus infection during pregnancy increases an infant’s risk of early-onset sepsis.7 Late-
onset neonatal sepsis occurs after day eight of life and is acquired after delivery.7 Having a
catheter in a blood vessel and/or staying in the hospital for an extended period of time
increases an infant’s risk of sepsis after delivery.7
The chances of survival are reduced for newborns with a serious infection regardless of
whether they are hospitalized or in the community.9 Therefore, the complications of neonatal
sepsis may be death or lifelong disability. Identifying and diagnosing neonatal sepsis is
difficult because sick newborns often present with non-specific signs and symptoms that
vary from changes in body temperature, breathing problems, diarrhea, low blood sugar,
reduced movements and sucking, seizures, slow heart rate, swollen belly area, vomiting, and
jaundice.7,9
1.1.3 Birth Asphyxia
One of the most common birth complications is RDS where babies struggle to breathe
because their immature lungs do not produce enough surfactant, a protein that keeps small
air sacs in the lungs from collapsing. Birth asphyxia, defined as the failure to establish
breathing or perfusion at birth, accounts for an estimated 900 000 deaths per year. 10
Complications of low oxygen intake include damage to the brain tissues that can cause
seizures and other neurological problems. The clinical presentation is not specific to birth
asphyxia and the preferred term is “neonatal encephalopathy”, where the precise cause is
not implied.11 Possible antecedents for neonatal encephalopathy include infection, cerebral
infarction, intracranial haemorrhage, congenital brain malformations, inborn errors of
metabolism, and genetic syndromes. However, the most likely antecedent is hypoxia-
ischaemia (19 to 52%) that arise from birth asphyxia.11 Neonatal encephalopathy is clinically
assessed into three Sarnat staging where stage 1 may likely have unaffected outcome, stage 2
where 25% develop cerebral palsy, and stage 3 often results in disability or death.11
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-8
1.2 Neonatal Conditions: Burden of Disease
The neonatal period is only 28 days and yet accounts for 40% of all deaths in children
younger than five years.4 The average daily mortality rate during the neonatal period is
almost 30-times higher than during the post-natal period.6 Furthermore, there is still
variation within the neonatal period such that mortality is very high in the first 24 hours
after birth (25 to 45% of all neonatal deaths) while three quarters of neonatal deaths happen
in the first week after birth.6,12
Neonatal conditions exert a heavy burden on families, society, and the health system. With
the most potential for years lived with disability (YLD) and years of life lost (YLL), neonatal
conditions are significant DALYs contributors.
1.3 Global Burden of Disease
Over past decades, neonatal mortality along with under-five mortality has been slowly
decreasing. Globally, the number of neonatal deaths has decreased from 4 362 000 in 1990 to
2 955 000 in 2011.13 However, all regions have seen slower reductions in neonatal mortality
compared to under-five mortality resulting in an increased share of neonatal deaths among
the under-five deaths. Neonatal deaths accounted for 36% of the under-five deaths in 1990
and rose to 40% in 2010.4 This trend is expected to continue.13
The Millennium Development Goal (MDG) 4 calls for a reduction in the under-five mortality
rate by two-thirds between 1990 and 2015.3 Even with the visible progress, the rate of decline
is insufficient to reach the set targets, particularly in sub-Saharan Africa and South Asia.3
Child survival programs have primarily focused on causes of death after the neonatal period
such as pneumonia, diarrhea, malaria, and vaccine-preventable diseases. 14 The lack of
attention to neonatal conditions such as preterm birth, neonatal sepsis, and birth asphyxia,
has resulted in it accounting for an increasing proportion of under-five deaths.15 Unless
actions are taken to reduce neonatal deaths, neonatal conditions will remain a barrier to
progress on MDG 4.
An estimated 15 million babies in the world were born preterm in 2010, of which over one
million children die each year due to complications of preterm birth.3 For the newborns that
survive this often means a lifetime of significant disability.1 There is a dramatic survival gap
for premature babies depending on where they are born. A 10:90 survival gap exists where
over 90% of preterm babies born in low-income countries die within the first few days of life
while less than 10% of babies of this gestation die in high-income settings.3 Furthermore,
over 60% of preterm births occur in Africa and South Asia and of the 11 countries with
preterm birth rates of over 15%, all but two are in sub-Saharan Africa (Table 6.23.1).3 The
proportion of deaths due to prematurity drops with increasing neonatal mortality rate
(NMR); however, this pattern is due to the large number of deaths from infection in high
NMR settings.12
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-9
Table 6.23.1. Neonatal deaths by region, 2011
Region Number of neonatal
deaths (thousands)
Neonatal deaths as a share
of under-five deaths (%)
Developed regions 53 55
Developing regions 2 902 43
Northern Africa 40 47
Sub-Saharan Africa 1 122 33
Latin America & the Caribbean 107 53
Caucasus & Central Asia 28 39
Eastern Asia 151 57
Southern Asia 1 216 52
South-Eastern Asia 155 50
Western Asia 77 49
Oceania 5 40
World 2 955 43
Source: Adapted from Born Too Soon Report: The Global Action Report on Preterm Birth3
Female neonates have a well-described biological survival advantage in the neonatal
period.13 This pattern is reflected in the mortality trends for preterm deaths, particularly in
neonates aged 0-6 days (Figure 6.23.2). Not surprisingly, the NMR (neonatal mortality rate)
for neonates aged 0-6 days is consistently higher compared to neonates aged 7-27 days.
There has been progress in reducing the global deaths from complications of preterm birth
from a million since 1990, particularly in neonates aged 0-6 days, but much progress still
needs to be made.
Figure 6.23.2. Global neonatal mortality rates from complications of preterm birth
Source: Adapted from Global Burden of Disease Study 2010 Results by Cause and Region 1990-201016
0
5,000
10,000
15,000
20,000
25,000
30,000
35,000
40,000
45,000
50,000
1990 2005 2010 1990 2005 2010
Neonates: 0-6 days Neonates: 7-27 days
NM
R (
pe
r 1
00
,00
0)
Preterm Neonatal Mortality Rate - Global
Male
Female
Both
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-10
More than one-third of the estimated four million neonatal deaths each year are caused by
severe infections, and a quarter, an equivalent of one million neonatal deaths, are due to
neonatal sepsis and pneumonia alone.9 The risk of dying due to severe infection in high
mortality countries (NMR >45) is roughly 11-fold the risk in low-mortality countries (NMR
<15).6 The under-recognition of neonatal sepsis, delay in care seeking by the family, and lack
of access to appropriate services means that not much progress has been made since 1990
(Figure 6.23.3).9
Figure 6.23.3. Global neonatal mortality rates from neonatal sepsis
Source: Adapted from Global Burden of Disease Study 2010 Results by Cause and Region 1990-201016
Neonatal deaths from birth asphyxia are the fifth most common cause of under-five child
deaths after pneumonia, diarrhea, preterm birth complications, and neonatal infectons.4 The
Global Burden of Disease 2004 report allocated 42 million DALYs to birth asphyxia, which is
twice the number of DALYs allocated to diabetes and around 75% of the DALYs allocated to
HIV/AIDS.1 The risk of dying due to birth asphyxia is roughly eight-fold for babies in
countries with very high NMRs, even though the proportion of neonatal deaths is fairly
constant across mortality levels.
Consistent with the other neonatal conditions, NMR are much higher in boys than in girls
(Figure 6.23.4). This gender gap is more prominent in neonates aged 0-6 days compared to
neonates aged 7-27 days. Not surprisingly, the overall NMR for neonates aged 0-6 is
consistently higher compared to neonates aged 7-27 days. There has been progress in
reducing the global DALY from complications of preterm birth from a million since 1990,
particularly in neonates aged 0-6 days, but much progress still needs to be made.
0
2,000
4,000
6,000
8,000
10,000
12,000
14,000
16,000
18,000
20,000
1990 2005 2010 1990 2005 2010
Neonates: 0-6 days Neonates: 7-27 days
NM
R (
pe
r 1
00
,00
0)
Neonatal Sepsis Mortality Rate - Global
Male
Female
Both
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-11
Figure 6.23.4. Global neonatal mortality rates from encephalopathy as a result of birth
asphyxia and birth trauma
Source: Adapted from Global Burden of Disease Study 2010 Results by Cause and Region 1990-201016
1.4 EU/EEA Burden of Disease
The number of neonatal deaths in the EU has decreased from 169 999 in 1990 to 70 000 in
2011.13 However, there are large disparities even within the region where the highest national
mortality rate is estimated to be 40 times the lowest.17 Eastern Europe consistently has higher
mortality and DALYs in comparison to Western and Central Europe across all three neonatal
conditions, particularly neonatal sepsis and neonatal encephalopathy (Figure 6.23.5-7). The
greatest progress from 1990 to 2010 was seen in neonates aged 0-6 days compared to
neonates aged 7-27 days across the neonatal conditions. However, the number of deaths and
DALYs in neonates aged 0-7 days were much higher when compared to neonates aged 7-27
days. The gender survival gap is still consistent with the European data which show that
girls have a survival advantage compared to boys.16
0
5,000
10,000
15,000
20,000
25,000
30,000
1990 2005 2010 1990 2005 2010
Neonates: 0-6 days Neonates: 7-27 days
NM
R (
pe
r 1
00
,00
0)
Neonatal Encephalopathy Mortality Rate - Global
Male
Female
Both
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-12
1.4.1 Preterm birth
In a systematic review study, Europe was found to have the lowest rate of preterm birth (6.2%
of all births) compared to all other regions.3 However, mortality rates vary even within the
region. An estimated 4 506 deaths due to preterm birth complications occurred in Western
Europe, 4 835 deaths in Eastern Europe, and 1 876 deaths in Central Europe in 2010.16
Figure 6.23.5. Neonatal mortality rates from complications of preterm birth in Europe
Source: Adapted from Global Burden of Disease Study 2010 Results by Cause and Region 1990-201016
0
5,000
10,000
15,000
20,000
25,000
19
90
20
05
20
10
19
90
20
05
20
10
19
90
20
05
20
10
19
90
20
05
20
10
19
90
20
05
20
10
19
90
20
05
20
10
Neonates: 0-6days
Neonates: 7-27 days
Neonates: 0-6days
Neonates: 7-27 days
Neonates: 0-6days
Neonates:7-27 days
Western Europe Central Europe Eastern Europe
NM
R (
pe
r 1
00
,00
0)
Preterm Neonatal Mortality Rate - Europe
Male
Female
Both
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-13
1.4.2 Sepsis
Most neonatal sepsis deaths are in Eastern Europe, both in neonates aged 0-6 days and
neonates aged 7-27 days. With neonatal sepsis, the survival rate of girls is much higher than
boys. The largest gender difference in survival rates is seen in neonatal sepsis compared to
preterm birth and birth asphyxia. Mortality rates vary even within the region. An estimated
571 deaths due neonatal sepsis occurred in Western Europe, 1 417 deaths in Eastern Europe,
and 208 deaths in Central Europe in 2010.16
Figure 6.23.6. Neonatal mortality rates from neonatal sepsis in Europe
Source: Adapted from Global Burden of Disease Study 2010 Results by Cause and Region 1990-201016
0
500
1000
1500
2000
2500
3000
3500
4000
19
90
20
05
20
10
19
90
20
05
20
10
19
90
20
05
20
10
19
90
20
05
20
10
19
90
20
05
20
10
19
90
20
05
20
10
Neonates: 0-6days
Neonates: 7-27days
Neonates: 0-6days
Neonates: 7-27days
Neonates: 0-6days
Neonates: 7-27 days
Western Europe Central Europe Eastern Europe
NM
R (
pe
r 1
00
,00
0)
Neonatal Sepsis Mortality Rate - Europe
Male
Female
Both
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-14
1.4.3 Encephalopathy
The DALY burden from neonatal encephalopathy is disproportionately heavy in Eastern
Europe compared to Western and Central Europe such that despite having the largest
progress in neonates aged 0-6 days, Eastern Europe still has the highest DALY burden with
325 898.16 Central Europe has the lowest DALY burden of 44 455, while Western Europe has
a DALY burden of 153 542.16
Figure 6.23.7. Neonatal mortality rates from neonatal encephalopathy as a result of birth
asphyxia and birth trauma in Europe
Source: Adapted from Global Burden of Disease Study 2010 Results by Cause and Region 1990-201016
0
2,000
4,000
6,000
8,000
10,000
12,000
14,000
16,000
18,000
19
90
20
05
20
10
19
90
20
05
20
10
19
90
20
05
20
10
19
90
20
05
20
10
19
90
20
05
20
10
19
90
20
05
20
10
Neonates: 0-6days
Neonates: 7-27 days
Neonates: 0-6days
Neonates: 7-27 days
Neonates: 0-6days
Neonates:7-27 days
Western Europe Central Europe Eastern Europe
NM
R (
pe
r 1
00
,00
0)
Neonatal Encephalopathy Mortality Rate - Europe
Male
Female
Both
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-15
2. Control Strategy
2.1 Vaccination (Prevention)
Neonatal immunization has long been considered as a method for reducing neonatal
infections. However, the response varies according to the antigen and maternal antibodies
often interfere with a neonate’s response to the vaccine when administered under six
months.8 Protein antigen vaccines given at birth show poor responses compared to the same
antigen given at two months of age. 18 Vaccines targeting S. agalactiae and Streptococcus
pneumonia are shown to be ineffective when given in the neonatal period.19 However, herd
immunity effects have been seen in infants too young to receive when the heptavalent
pneumococcal conjugate vaccine (PCV7) was recommended for all children aged 2 to 23
months.20
There are no available vaccines for premature birth, neonatal sepsis, or neonatal asphyxia for
neonates, but some preventative recommendations include vaccinating the mother-to-be by
promoting vaccination of all children and adolescents.3 Infections transmitted around the
time of conception may result in preterm birth. 21 Maternal immunization can provide
neonates with the appropriate antibodies as soon as they are born.18 For example, studies of
maternal immunization with S. agalactiae type III conjugate vaccine have demonstrated
effective placental transfer and persistence of protective levels in two-month old infants.18
Through a recent modeling study, maternal immunization with S. agalactiae vaccine would
prevent 60-70% of neonatal S. agalactiae infections within the United States context alone.22
Encouraging results and promising safety profiles are also emerging from preliminary
studies of maternal immunization with pneumococcal polysaccharide and conjugate
vaccines.18,23 Furthermore, Novartis have recently completed a Phase II GBS vaccine which is
being trialed in the second trimester to prevent neonatal infection.24 The study is to evaluate
the safety and immunogenicity of GBS vaccine at one dose in healthy non-pregnant women
and eventually in three different doses in healthy pregnant women.24 However, barriers to
maternal immunization still exists, including liability issues for vaccine manufacturers in
developed countries, education of the public and health care providers regarding the benefits
of maternal immunization and poor ascertainment of data from low-income countries.18
Box 6.23.1: Maternal and Neonatal Tetanus elimination Maternal and neonatal tetanus deaths were among the most common lethal consequences of unclean
deliveries and umbilical cord care practices. Mortality rates are extremely high once tetanus is diagnosed,
especially when appropriate medical care is not available.
In 1988, WHO estimated that 787 000 newborns died of neonatal tetanus, roughly 6.7 deaths per 1 000
live births. Being a substantial public health problem, neonatal tetanus elimination was listed as one of
the goals at the 1990 World Summit for Children and again at the 44th World Health Assembly in 1991.
Through immunization of pregnant and child bearing age women and promotion of hygienic deliveries,
WHO estimates that only 58 000 newborns died from neonatal tetanus in 2010 – a 93% reduction from
the 1980s.
Source: Maternal and Neonatal Tetanus (MNT) elimination. [Internet]. [cited 14 February 2013].
Available from: http://www.who.int/immunization_monitoring/diseases/MNTE_initiative/en/index.html
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-16
2.2 Other Preventative Approaches
2.2.1 Preterm birth
Alternative methods have been developed to help prevent preterm birth targeting from
preconception to antenatal care. This includes a preconception care package that includes
family planning (e.g. birth spacing and adolescent-friendly services), education and nutrition
especially for girls of child bearing age, and STI prevention.3 An antenatal care package is
recommended for all women that includes screening for and management of STIs, high
blood pressure, and diabetes; behavior change for lifestyle risks; and targeted care of women
at increased risk of preterm birth.3 Preconception care services for prevention of preterm
birth recommended for all women include:3
Prevent unintended pregnancies and promote optimal birth spacing – Women who
have very closely spaced pregnancies (within six months of a previous live birth or
pregnancy) are at higher risk of a preterm or low-birthweight babies.25 Correct and
consistent use of family planning and contraceptive methods (hormonal and barrier
methods) leads to more women spacing their pregnancies 18 to 24 months apart,
which is ideal.26 Breastfeeding is an underused method for preventing closely spaced
pregnancies and should be promoted for 24 months. Twelve months of contraceptive
use along with breastfeeding reduces the risk of mortality for the next newborn by
68.4%.26
Optimize pre-pregnancy weight – Women who are underweight before pregnancy
(body mass index less than 18.5 kg/m2) and women who are overweight/obese (body
mass index greater than 25 kg/m2) are at significantly greater risk of having
premature, low birth weight newborns.27,28 Improving food security particularly in
impoverished nations, and achieving a healthy maternal weight could reduce the
rates of preterm birth.
Promote healthy nutrition including supplementation/fortification of essential
foods with micronutrients – Studies of the biological mechanisms leading to preterm
birth suggest that more severe congenital disorders such as neural tube defects, might
result in preterm delivery.28 Consuming multivitamins in the preconception period
has been shown to help prevent neural tube and other birth defects.29 Iron and folic
acid fortification of foods for mass consumption is considered an important strategy
to increase micronutrient levels in that population.3
Promote vaccination of children and adolescents – Infections transmitted around the
time of conception or during pregnancy may result in preterm birth. 30 Many
infections, such as rubella, could be prevented through routine childhood
vaccinations.3
In addition to the following care services, women with special risk factors that increase the
risk for preterm birth should also be recommended3:
Screen for, diagnose and manage mental health disorders and prevent intimate
partner violence – Maternal stressors including depression, socioeconomic hardship
and intimate partner violence have been linked to preterm birth.31,32 Studies suggest
that stress acts through inflammatory pathways involving maternal cortisol which
causes premature birth. 33 , 34 Furthermore, women with stressors have a greater
likelihood to engage in risky behaviors such as smoking and alcohol use.35
Prevent and treat sexually transmitted infections (STI)s, including HIV/AIDS –
Reducing infectious diseases, particularly syphilis, can lower the rates of stillbirths
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-17
and preterm birth.36 Behavioral, counseling, and mass treatment interventions with
antibiotics have been shown to decrease the prevalence of STIs.37,38
Promote cessation of tobacco use and restrict exposure to secondhand smoke –
Cigarette smoking roughly doubles the risk of preterm birth.39 Tobacco cessation
interventions and preconception counseling involving the husbands or partners can
increase the number of women who quit smoking and reduce the exposure to
secondhand-smoke.40
As of February 2011, Makena® (17-alpha-hydroxyprogesterone caproate or 17P) was
approved by the US FDA as a pharmaceutical drug for the reduction of the risk of certain
preterm births in women who have had at least one prior preterm birth.41 Weekly injections
of 17P resulted in significant reduction in the risk of delivery at less than 37 weeks of
gestation (RR=0.66, 95% CI: 0.45 to 0.81), delivery at less than 35 weeks of gestation (RR=0.67,
95% CI:0.48 to 0.93), and delivery at less than 32 weeks of gestation (RR=0.58, 95%CI:0.37 to
0.91).42 So far, this is the only pharmaceutical drug available in preventing preterm birth and
has only been approved in the United States.
2.2.2 Sepsis
Although there is no way to prevent all types of sepsis, the transmission of Group B
streptococcal (GBS) bacteria from mother to child could be prevented.43 If a woman tests
positive for GBS, she can receive intravenous antibiotics during labor, optimally at least four
hours before delivery.43
In addition to maternal treatments, prophylactic approaches have also been considered. Any
women with a fever during labor, pPROM, or if they had other children with sepsis or other
diseases triggered by GBS are recommended to receive intravenous antibiotics during labor
to lower the risk of transmission to the child.22 Intrapartum antibiotic prophylaxis has been
highly effective in reducing both early-onset neonatal bacterial and maternal sepsis in
developing countries.44 For example, chemoprophylaxis has halved the incidence of early-
onset neonatal S. agalactiae sepsis from 1.7 per 1 000 live births in 1993 to 0.6 per 1 000 in 1998
in the United States.45
In addition, hand washing and ensuring that those who come in contact with the newborn
are not sick and have been fully vaccinated can also prevent infection in both home and
health facility settings.19 Although, both important, there is stronger evidence for hand
washing by health care providers after delivery for reducing neonatal sepsis and infection
rates in hospitals compared to hand washing in mothers of their own infants.46,47 There is
emerging evidence that neonatal skin antisepsis preparations, such as sunflower seed oil and
chlorhexidine, provides cheap, safe, and effective protection against nosocomial infections in
hospitalized preterm neonates in studies in South Asia.8,48,49
Lastly, neonatal nutrition can be a protective factor in neonatal infections. Breast milk
contains secretory IgA, lysozymes, white blood cells, and lactoferrin and has been shown to
promote the growth of healthy Lactobacilli and reduce the growth of E. coli and other Gram-
negative pathogenic bacteria.19 Early initiation and exclusive breastfeeding is associated with
significant reductions in diarrhea and acute respiratory infections in neonates while other
observational studies have demonstrated impact on infection specific mortality rates during
the neonatal period.50,51,52 Trials of parenteral vitamin A supplementation have also shown
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-18
significant reductions in respiratory disease in low birth-weight infants and reductions in
neonatal mortality.53,54
2.3 Diagnostic Testing
2.3.1 Sepsis
Neonatal clinical sepsis syndrome identification is difficult since the symptoms are often
very similar to other life-threatening diseases such as necrotizing enterocolitis, perinatal
asphyxia, and hyaline membrane disease.55,56 Seven danger signs have been identified to be
used to diagnose infants with very severe disease including neonatal sepsis (Table 6.23.2)
and have now been incorporated into the new neonatal WHO Integrated Management of
Childhood Illness guidelines.56 These signs provide high sensitivity and moderate specificity
for detecting serious illness.
Table 6.23.2. Clinical symptoms and signs of severe neonatal illness including sepsis
History of difficulty feeding
History of convulsion
Movement only when stimulated
Respiratory rate ≥60 breaths per minute
Severe chest indrawing
Axillary temperature ≥37.5˚C
Axillary temperature <35.5˚C
Source: Adapted from Clinical signs that predict severe illness in children under age two months56
Laboratory tests can help diagnose neonatal sepsis and identify the specific bacteria causing
the infection. Blood tests may include blood culture, C-reactive, protein, and complete blood
count.7 If necessary, a lumbar puncture will be done to examine the cerebrospinal fluid for
bacteria.7 If the baby has a cough or issues breathing, a chest x-ray will be taken and urine
culture tests can be done if the baby is older than several days.7 However, identification of
pathogenic organisms remain difficult because bacterial load in neonates may be low due to
mothers receiving antepartum or intrapartum antibiotics and also because only small
amounts of blood can often be taken from newborns.57 Contamination rates may also be high
due to difficulties of performing sterile venipuncture in small babies.8
Conventional assays are being replaced by newer “real-time” systems that are faster and
associated with lower contamination rates because amplification and detection occur
simultaneously in a closed system.58 The real-time polymerase chain reaction (PCR) produces
quantitative results within 30 minutes and calculates bacterial load by using a single primer
to detect the universal bacterial genome (16S RNA or 23S RNA).59 Broad-range real-time PCR
can distinguish bacterial septicaemic disease from other causes of neonatal illness with
similar symptoms such as asphyxia or premature complications.59 Alternatively, multiplex
PCR amplifies different targets, but is focused only on specific pathogens.60 However, real
time PCR requires the specimen to be collected with a sterile venipuncture which may be
difficult in neonates. Typically, the specimen is collected via capillary heel prick due to its
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-19
ease, but also has the highest potential for contamination by skin flora.8 Furthermore, real-
time PCR technolgoies are expensive and can only be used by highly trained staff.8
Antigen detection techniques allow for rapid detection and identification without culturing.8
The most commonly used commercially available test is the latex agglutination assay which
is dependent on specific agglutination by bacterial cell wall antigens of antibody-coated latex
particles.8 However, these tests are reliable in detecting limited organisms such as S.
agalactiae and are associated with high false positive and negative rates.61
Despite diagnostic advances, none of these diagnostic tests are ideal with results of blood
culture being delayed up to 48 hours.3 Since the condition of a neonate with true sepsis can
deteriorate quickly, broad-spectrum antibiotic therapy are often prescribed even before the
test results are available.22,56 This often results in unnecessary antibiotic use, which may
contribute to the emergence of antibiotic resistance.22
2.4 Treatment
2.4.1 Preterm birth
In women with preterm labor, tocolytics are drugs used to suppress uterine contractions and
are often given to delay birth by inhibiting uterine contractions. Several tocolytics are
available that work to inhibit preterm labor via different mechanisms including oxytocin
antagonists, betamimetics, calcium channel blockers, and magnesium sulphate.3 The
provision of tocolytics has been shown effective in suppressing labor to allow enough time
for antenatal corticosteroid treatment for fetal lung maturation prior to delivery and/or to
transfer mother and baby to a higher-level facility where appropriate care may be
available.3, 62 Although betamimetics have been shown to delay delivery, its effects on
neonatal outcomes and fetal maternal side effects have not been shown to improve perinatal
outcome and have high frequency of unpleasant and sometimes fatal maternal side effects.63
Any use of strategies to prolong labor must be evaluated against the potential risk of
prolonged exposure of mother and fetus to sub-optimal conditions that may result in harm.3
According to Cochrane systematic reviews, there are several pharmaceutical interventions
which are effective in delaying delivery by at least two days after the initiation of preterm
labor (Figure 6.23.8). Trans-abdominal amnioinfusion reduces the risk of delivery within
seven days of treatment compared with the control group in women with pPROM (Relative
risk (RR) = 0.18, 95% confidence interval (CI): 0.05 to 0.7).64 The most common drugs used to
stop preterm labor are betamimetics such as ritodrine and terbutaline, as well as magnesium
sulphate.65 However, another Cochrane Review showed that calcium channel blockers, such
as nifedipine and nicardipine, may be more effective in delaying delivery within seven days
of treatment compared with other more commonly used betamimetics (RR=0.76, 95% CI: 0.6
to 0.97).65 Lastly, any tocolytic administration seem to reduce births within 48 hours of
treatment compared to no treatment at all (RR=0.55, 95% CI: 0.32 to 0.95). 66 All these
pharmaceutical interventions seem to be effective in delaying delivery long enough to allow
for a 48-hour corticosteroid treatment for fetal maturation, hopefully, reducing the morbidity
and mortality associated with prematurity. A recent systematic review and network meta-
analysis conducted by Haas et al. showed that prostaglandin inhibitors (OR=5.39, 95% CI:
2.14 to 12.34) followed by magnesium sulfate (OR=2.76, 95% CI: 1.58 to 4.94), calcium channel
blockers (OR=2.71, 95% CI: 1.17 to 5.91), beta mimetics (OR=2.41, 95% CI: 1.27 to 4.55), and
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-20
oxytocin receptor blocker (OR=2.02, 95% CI: 1.10 to 3.80) delayed delivery best by 48 hours
when compared with placebo.67
Figure 6.23.8. Pharmaceutical interventions for delaying delivery by at least two days.
In contrast to interventions given after the initiation of preterm labor, several pharmaceutical
interventions exist in preventing delivery prior to 37 weeks of gestation (Figure 6.23.9). The
treatment methods vary depending on the potential risk of preterm birth. A Cochrane
Review of antibiotic treatment for bacterial vaginosis before 20 weeks of gestation suggest
reductions in the risk of preterm birth (OR=0.72, 95% CI: 0.55 to 0.95).68 However, there is
little evidence that treating all pregnant women with bacterial vaginosis, including those
beyond 20 weeks of gestation, is effective in preventing preterm birth. Vaginal antibiotic
treatments, oral antibiotic treatments, and clindamycin (oral or vaginal) treatments did not
show significant reduction in the risk of preterm birth compared to no treatment (OR=0.88,
95% CI: 0.64 to 1.21; OR=0.9, 95% CI: 0.75 to 1.08; OR=0.8, 95% CI: 0.6 to 1.05; respectively).68
Another Cochrane Review of prophylactic antibiotic treatment during the second or third
trimester of pregnancy reduced the risk of preterm delivery compared to the placebo group
(RR=0.64, 95% CI: 0.47 to 0.88).69 However, there was substantial bias in the review’s results,
warranting further research. Furthermore, a Cochrane Review compared non-selective cyclo-
oxygenase (COX) inhibitors, such as indomethacin, with either placebo and other tocolytics.
The results suggest reduced risk of preterm labor using COX inhibitor compared to both
placebo and other tocolytics (RR=0.21, 95% CI:0.07 to 0.62; RR=0.53, 95% CI: 0.31 to 0.94;
respectively).70 It should be noted, however, that trial size was small and that the results, as
well as the potential adverse effects of COX inhibition could not be adequately assessed.70
For some women, an episode of preterm labor settles and does not result in immediate
0
0.2
0.4
0.6
0.8
1
1.2
transabdominal amnioinfusionVS no amniofusion [1]
calcium channel blockers(nifedipine) VS betamimetic [2] tocolytic VS no tocolytic [3]
Re
lati
ve R
isk
wit
h 9
5%
CI
Interventions
Pharmaceutical Interventions for Preterm Birth
[#] Cochrane Review (year): trials (subjects) [1] Hofmeyr et al. Amnioinfusion for preterm premature rupture of membranes (2011): 1(34) [2] King et al. Calcium channel blockers for inhibiting preterm labor (2003): 12(1029) [3] Mackeen et al. Tocolytics for preterm premature rupture of membranes (2011): 6(354)
OUTCOME: Delivery within 7 days of tx
<1 =
fav
ors
tre
atm
ent
>1 =
fav
ors
co
ntr
ol
OUTCOME: Delivery within 2 days of tx
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-21
birth.71 Maintenance therapy with oxytocin receptor antagonist such as atosiban may have
the potential to prevent premature birth. However, Cochrane Reviews of this treatment
compared to placebo or no treatment did not provide enough evidence that maintenance
treatment reduced the risk of preterm birth (RR=0.89, 95% CI:0.71 to 1.12).71 Lastly, a double-
blind, placebo-controlled trial showed that treatment with 17P significantly reduced the risk
of delivery at less than 37 weeks of gestation (RR=0.66, 95% CI: 0.54 to 0.81).
Figure 6.23.9. Pharmaceutical intervention for preventing preterm birth defined as 37
weeks of gestation.
Currently, there are three key interventions that can be delivered during the pregnancy
period with evidence of improving health outcomes in a premature baby: antenatal
corticosteroids, antibiotics for pPROM, and magnesium sulphate (Table 6.23.3).3
0
0.2
0.4
0.6
0.8
1
1.2
1.4
antibiotics VSplacebo/no
treatment [1a]
vaginalantibiotics VSplacebo/no
treatment [1b]
oral antibioticsVS placebo/notreatment [1c]
clindamycin(oral or
vaginal) VSplacebo/no
treatment [1d]oral antibioticsVS placebo [2]
indomethacin(non-selectiveCOX inhibitor),
nimesulide,sulindac,
ketorolac,rofecoxib VSplacebo [3a]
indomethacin(non-selectiveCOX inhibitor),
nimesulide,sulindac,
ketorolac,rofecoxib VS
other tocolytic[3b]
subcutaneuosatosiban VSplacebo [4]
17P VS placebo[5]
Re
lati
ve R
isk/
Od
ds
Rat
io w
ith
95
% C
I
Pharmaceutical Interventions for Preterm Birth OUTCOME: Preterm birth (<37 weeks)
>1 =
fav
ors
co
ntr
ol
<1 =
fav
ors
tre
atm
ent
Odds ratio Relative Risk
>1 =
fav
ors
co
ntr
ol
<1 =
fav
ors
tre
atm
ent
[#] Cochrane Review (year): trials (subjects) [1] McDonald et al. Antibiotics for treating bacterial vaginosis in pregnancy (2007): (a) 5(2387) (b) 5(1921) (c) 8(4069) (d) 6(2406) [2] Thinkhamrop et al. Prophylactic antibiotic administration during second and third trimester in pregnancy for preventing infectious morbidity and mortality (2002): 1(258) [3] King et al. Cyclo-oxygenase inhibitors for treating preterm labor (2005):
(a) 1(36) (b) 8(557) [4] Papatsonis et al. Maintenance therapy with oxytocin antagonists for inhibiting preterm birth after threatened preterm labour (2009): 1(513)
[#] Article (year)
[5] Meis et al. Prevention of Recurrent Preterm Delivery by 17 Alpha-Hydroxyprogesterone
Caproate (2012)
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-22
Antenatal corticosteroids can be administered to women at high risk of preterm birth as early
as 23 weeks and can significantly reduce the premature baby’s risk of death, respiratory
distress, and developmental problems.3 The WHO lists antenatal corticosteroids
(betamethasone and dexamethasone) as a priority intervention for the prevention of
respiratory distress syndrome (RDS) in premature babies and considers antenatal
corticosteroids as a priority medicine for reducing mortality among premature babies.72 It
should be noted that at the time of publication, dexamethasone was listed for treating
allergies only. Despite the evidence of effectiveness, antenatal corticosteroid use remains low.
In 2000, it was estimated that in the 42 countries with 90% of the world’s childhood deaths,
only 5% of appropriate candidates received the intervention.73 This is a clear indication of
missed opportunities for improving the survival chances of premature babies.
Premature rupture of the membranes is strongly associated with infection of the amniotic
membranes contributing to preterm birth and other poor fetal outcomes such as cerebral
palsy and chronic lung disease.3 Antibiotic treatment for pPROM has been shown to
suppress labor for up to 48 hours as well as reduce neonatal infections and abnormal cerebral
ultrasound scans prior to hospital discharge.3 However, due to increasing concern around
bacterial resistance and the risk of maternal anaphylaxis with antibiotic use, its risks and
benefits should be assessed to ensure judicious use of antibiotics.
Magnesium sulphate administration to women at risk of preterm birth reduces the risk of
neurological disorders in their infants such as cerebral palsy and improve long-term neonatal
health outcomes.3,74 It is a safe and relatively inexpensive drug.74 However, magnesium
sulphate has a narrow safe dosage range and require close monitoring during treatment.43
Further studies are needed to investigate the maternal side effects (e.g. flushing, sweating,
nausea, vomiting, headaches, and a rapid heartbeat).3
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-23
Table 6.23.3. Common medicines for preterm labor
Medicine
Possible maternal side
effects Possible side effects in baby
Co
rtic
ost
ero
id
Betamethasone Fluid build-up in the body
Rising blood pressure
Increased risk of infection
Problems with wound
healing
Increased risk of infection
Dexamethasone Fluid build-up in the body
Rising blood pressure
Increased risk of infection
Problems with wound healing
Increased risk of infection
To
coly
tic
Calcium channel
blockers (nifedipine)
Redness of the skin
Headache
Dizziness or feeling faint
Nausea
Low blood pressure
Constipation or diarrhea
No known side effects
Nonsteroidal anti-
inflammatory drugs
(indomethacin)
Dizziness
Nausea or throwing up
Heartburn
Vaginal bleeding
Swollen stomach lining
Oligohydramnios
Ductus arteriosis
Rising blood pressure in
the lungs
Kidney problems
Bleeding within the brain
or heart
Jaundice
Necrotizing enterocolitis
Magnesium sulfate Fast or irregular heartbeat
Fluid in the lungs
Low blood pressure
High blood sugar
Low blood potassium
Trouble breathing
Chest pain
Shaking or feeling nervous
Seizure
Nausea or throwing up
Headache
Dizziness
Fever
Diarrhea
Fast heartbeat
Source: Adapted from March of Dimes, Preterm labor75
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-24
2.4.2 Sepsis
Antibiotics are used to prevent life-threatening complications from infections for both the
mother and the baby. Since early-onset neonatal sepsis is caused by infection from the
mother before or during the delivery, antenatal and intrapartum interventions targeting the
mother is common to reduce the risk of neonatal sepsis (Figure 6.23.10). Prelabour rupture of
the membranes increases the risk of infection for the woman and her baby.76 A Cochrane
Review of amnioinfusion treatment for pPROM showed reduction in neonatal sepsis
compared to no treatment in other women with pPROM (RR=0.26, 95% CI:0.11 to 0.61).64
Antibiotic treatment is accepted as the standard of care, but routine use of prophylactic
antibiotics for women at the time of pPROM raises concern due to the increasing problems
with bacterial resistance and the risk of maternal anaphylaxis with antibiotic use.76 It should
be noted that reviews of prophylactic antibiotic use compared to placebo or no treatment
was associated with a reduction in neonatal sepsis, but the results did not reach statistically
significance (RR=0.14, 95% CI:0.02 to 1.13). 77 Antenatal corticosteroid treatment for
accelerating fetal lung maturation for women at risk of preterm birth has been shown to
reduce birth complications including the risk of neonatal sepsis (RR=0.56, 95% CI:0.38 to
0.85).78 Intraamniotic infection is also associated with neonatal sepsis and studies have been
conducted to examine the effectiveness of different antibiotic regimens to treat this infection.
Intrapartum antibiotic treatment was associated with a reduction in neonatal sepsis
compared to antibiotic treatment given immediately postpartum, but the results did not
reach statistical significance (RR=0.08, 95% CI:0.0 to 1.44).78
One intervention focused on the neonate exists in preventing neonatal infection in preterm
and/or low birth weight infants (Figure 6.23.10). Preterm infants are deficient in
immunoglobulin (IgG); therefore, prophylactic administration of intravenous
immunoglobulin may have the potential of preventing infections.79 According to a Cochrane
systematic review, the use of prophylactic intravenous immunoglobulin was statistically
significant for reducing sepsis (RR=0.85, 95% CI:0.74 to 0.98).79
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-25
Figure 6.23.10. Pharmaceutical interventions to reduce risk of developing neonatal sepsis
Several pharmaceutical interventions exist to treat neonatal sepsis once it develops. Prompt
antibiotic treatment is necessary as newborn babies have an immature immune system and
conditions can deteriorate quickly once sepsis is diagnosed.9 Cochrane Reviews were
gathered to assess the effectiveness of antibiotic regimens for treatment of neonatal sepsis
and the results are limited (Figure 6.23.11). Two small studies compared monotherapy
(ticarcillin or clavulanate) with combination therapy (piperacillin and gentamicin) and
showed no significant difference in mortality outcomes from neonatal sepsis (RR=0.75, 95%
CI:0.19 to 2.9).80 Another review assessed the effectiveness of beta-lactam therapy compared
with combination of beta-lactam plus aminoglycoside treatment and found that there was no
significant difference in mortality outcome between these two therapies (RR=0.17, 95%
CI:0.01 to 3.23).81
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
transabdominalamnioinfusion VS no
amniofusion [1]
prophylacticantibiotics VS
placebo/no treatment[2]
antenatalcorticosteroid VS
placebo/no treatment[3]
intrapartum antibioticsVS postpartumantibiotics [4]
IVIG VS no treatment[5]
Re
lati
ve R
isk
wit
h 9
5%
CI
Intervention
Pharmaceutical Interventions for Neonatal Sepsis OUTCOME: Neonatal sepsis
>1 =
fav
ou
rs c
on
tro
l <1
= f
avo
rs t
reat
men
t
[#] Cochrane Review (year): trials (subjects) [1] Hofmeyr et al. Amnioinfusion for preterm premature rupture of membranes (2011): 1(60) [2] Flenady et al. Antibiotics for prelabour rupture of membranes at or near term (2002): 2(838) [3] Roberts et al. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth (2006): 5(1319) [4] Hopkins et al. Antibiotic regimens for management of intraamniotic infection (2002): 1(45) [5] Ohlsson et al. Intravenous immunoglobulin for preventing infection in preterm and/or low birth weight infants (2004): 10(3975)
Neonatal intervention Maternal intervention
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-26
Figure 6.23.11. Pharmaceutical interventions for neonatal sepsis
Currently, parenteral (intravenous or intramuscular) regimens of a combination of
penicillin/ampicillin and gentamicin or third-generation cephalosporins (e.g. ceftriaxone or
cefotaxime) for 10 to 14 days is recommended by national paediatric associations and the
WHO (Table 6.23.4).8,82 These antibiotics are shown to be safe and retain efficacy when
administered at extended intervals.83 These treatments are effective against Streptococcus, but
Staphylococcus is highly resistant.84 Gram-negative antimicrobial susceptibility to ampicillin
and gentamicin can also be poor, particularly for Klebsiella.84 E.coli resistance to ampicillin,
gentamicin, and third-generation cephalosporins in hospitals of both developed and
developing countries is emerging and is raising concern. 85 Furthermore, parenteral
administration requires health care professionals that are often lacking in lower-resource
settings where the majority of births and neonatal deaths occur at home.86,87
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
monotherapy(Timentin) VScombination
therapy(Piperacillin andGentamicin) (1)
intramuscularpenicillin VSplacebo (2)
beta-lactam VSbeta-lactam +
aminoglycoside (3) IVIG VS placebo (4)ampicillin/penicillinvs no treatment (5)
Rel
ativ
e R
isk
wit
h 9
5%
co
nfi
den
ce in
terv
al
Intervention
Pharmaceutical Interventions for Neonatal Sepsis OUTCOME: Neonatal mortality
Neonatal intervention Maternal intervention
<1
= f
avo
rs t
reat
men
t >1
= f
avo
urs
co
ntr
ol
[#] Cochrane Review (year): trials (subjects) [1] Mtitimila et al. Antibiotic regimens for suspected early neonatal sepsis (2004): 1(72) [2] Woodgate et al. Intramuscular penicillin for the prevention of early onset group B streptococcal infection in newborn infants (2004): 1(1187) [3] Gordon et al. Antibiotic regimens for suspected late onset sepsis in newborn infants (2005): 1(24) [4] Ohlsson et al. Intravenous immunoglobulin for preventing infection in preterm and/or low birth weight infants (2004): 15(4125) [5] Ohlsson et al. Intrapartum antibiotics for known maternal Group B streptococcal colonization (2009): 3(500)
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-27
Table 6.23.4. Injectable antibiotics products for treating neonatal sepsis
Drug Procaine
benzylpenicillin Gentamicin Ceftriaxone
Indication Neonatal sepsis, first-line Neonatal sepsis,
second-line
Formulation
Powder for injection:
1 g (=1 mill IU); 3 g
(=3 mill IU) in vial
Injection: 10 mg; 40
mg (as sulfate)/ml in
2-ml vial
Powder for injection:
250 mg and 1 g
Dose
Intramuscular
injections 50 mg/kg
of ampicillin (or
comparable) every 6-
8 hours – depending
on age – divided
2x/day for at least 10
days
Intramuscular
injection 7.5 mg/kg of
gentamicin (or
comparable) in
addition to the
benzylpenicillin
injections – divided
2x/day for at least 10
days
50 mg/kg once daily
for all newborns (<1
week, <2 kg) 75
mg/kg once daily for
10 days (>1 week, >2
kg)
Average Cost
(per treatment)
~US$ 0.13-0.16 ~US$ 0.17-2.03 ~US$ 0.50-0.90
(dependent on weight and # days treated)
Source: Every Woman Every Child – Injectable Antibiotics for Newborn Sepsis88
Despite the existence of effective antibiotics to treat neonatal sepsis, case-fatality rates for
severe bacterial infections in developing countries remain high.88 Although relatively low-
cost treatments exist, properly trained care providers are required to administer them. There
has been insufficient focus on optimizing innovative approaches to product formulation and
packaging.121 Gentamicin administration should be monitored closely as there are risks
related to toxicity that could result in permanent hearing and kidney damage.88 In both Asia
and sub-Saharan Africa, where a large burden of neonatal sepsis lies, formulations at
appropriate dosage may not be readily available. 88 It is difficult to develop alternative
delivery mechanisms for these antibiotics as procaine benzylpenicillin and ceftriaxone
powders must be reconstituted with sterile water and achieving appropriate volumes with
the correct formulation remains a challenge.88 The UN Commissioners’ Report released in
2012 for life-saving commodities for women and children have identified and recommended
simple potential product innovations that demand further research particularly in the
administration of gentamicin (including fixed-dose presentations for needles and syringes,
auto-disable syringes, and micro-needle patch technology for administering gentamicin)
(Table 6.23.5).89
Table 6.23.5. Potential product innovations for injectable antibiotics
Commodity Potential product innovations
Injectable antibiotics Fixed-dose presentations for basic needles and syringes and
pre-filled delivery devices for administering gentamicin
Auto-disable syringes for administering gentamicin
Micro-needle patch technology for administering gentamicin
Source: UN Commission on Life-Saving Commodities for Women and Children121
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-28
2.4.3 Birth Asphyxia
Several pharmaceutical interventions have been identified to reduce the risk of neonatal
mortality from respiratory distress syndrome (RDS) (Figure 6.23.12). Respiratory distress
syndrome is associated with a deficiency or dysfunction of pulmonary surfactant that lines
the alveolar surface and prevents atelectasis at the end of expiration. Surfactant therapy has
been shown to improve the immediate need for respiratory support and the clinical outcome
of very preterm newborns. 90 , 91 Studies have been conducted on a variety of surfactant
preparations used to prevent (prophylactic or delivery room administration) or treat (very
early, selective or rescue administration).92,93 Use of surfactant therapy have demonstrated
decreases in the severity of respiratory distress, decreases in the frequency of pneumothorax,
increases survival without chronic lung disease, and decreases mortality.91 Cochrane
systematic reviews, show that the use of animal derived surfactant extract showed reduced
risk of neonatal mortality from RDS (RR=0.68, 95% CI:0.57 to 0.82). Inositol is an essential
nutrient which promotes maturation of several components of surfactant and may play a
critical role in reducing neonatal mortality in neonates with RDS. Cochrane Reviews of
inositol supplementation resulted in statistically significant reductions in neonatal mortality
(RR=0.53, 95% CI:0.31 to 0.91).94 Furthermore, lung edema may complicate RDS in preterm
infants and for this reason, treatment with diuretics like furosemide may help remove the
excess fluid from the lungs that can cause breathing problems.95 However, the data did not
support routine administration of furosemide in preterm infants with RDS as it did not
reduce the risk of neonatal mortality (RR=1.47, 95% CI: 0.72 to 2.97) and furosemide-induced
transient improvement in pulmonary function did not outweigh the increased risk for patent
ductus arteriosus and hemodynamic instability.95
Prophylactic administration of pulmonary surfactant to newborns at risk of developing RDS
is also another treatment option. The Cochrane Reviews of this intervention shows a
decrease in the risk of neonatal mortality in infants who receive prophylactic animal derived
surfactant extract compared to administration of normal saline or air placebo (RR=0.60, 95%
CI:0.47 to 0.77).96 A variety of synthetic surfactant products have also been developed and
administered prophylactically. Cochrane Reviews, supports prophylactic administration of
protein free synthetic surfactant in reducing the risk of neonatal mortality (RR=0.70, 95%
CI:0.58 to 0.85).97
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-29
Figure 6.23.12. Pharmaceutical interventions for preventing neonatal mortality from RDS
A variety of surfactant preparations have been developed and tested including synthetic
surfactants and surfactants derived from animal sources for treatment and prophylactic use
in infants at risk for or having RDS (Figure 6.23.13). Although both surfactant preparations
are effective, comparative reviews show that natural surfactants seem to have greater
efficacy, perhaps due to the protein content that is lacking in synthetic surfactants.96, 98
Cochrane Reviews comparing natural surfactant extract versus synthetic surfactant show
that there is greater efficacy of natural surfactant products (RR=0.87, 95% CI:0.76 to 0.98).96
Recent developments in synthetic surfactant preparations include peptides or whole proteins
that mimic endogenous surfactant protein.97 Comparisons of synthetic surfactant containing
surfactant protein mimics compared to animal derived surfactant extract showed
comparable results in reducing the risk of neonatal mortality (RR=0.79, 95% CI:0.61 to 1.02).97
Furthermore, it has been suggested that multiple doses of surfactant may lead to improved
outcome due to surfactant inactivation.99 Meta-analysis of trials comparing multiple doses
with only a single dose of animal derived surfactant extract as treatment in established RDS
suggests a reduction in the risk of mortality, but did not reach statistical significance
(RR=0.63, 95% CI:0.39 to 1.02). However, statistical significance was reached in a similar trial
comparing multiple doses with a single dose of prophylactic exogenous surfactant in infants
at high risk of RDS for reducing risk of neonatal death (RR=0.56, 95% CI:0.39 to 0.81).99
Although animal derived surfactant preparations seem to be the most effective in the
treatment of premature infants with RDS, they are expensive to produce and supplies are
limited.100 Table 6.23.6 highlights the cost of the bovine lung extract, beractant, and the
0
0.5
1
1.5
2
2.5
3
3.5
Furosemide (1)
Human amniotic fluidextract, calf lung
surfactant extract,modified bovine
surfactant exract,porcine surfactant
extract (2) Inositol (3)Animal derived
surfactant extract (4)Protein free synthetic
surfactant (5)
Re
lati
ive
Ris
k w
ith
95
% c
on
fid
en
ce in
terv
al
Pharmaceutical Interventions for RDS compared to placebo/no treatment OUTCOME : Neonatal mortality
Treatment Prophylaxis
Intervention
<1 =
fav
ors
tre
atm
ent
>1 =
fav
ors
co
ntr
ol
[#] Cochrane Review (year): trials (subjects) [1] Stewart et al. Diuretics for respiratory distress syndrome in preterm infants (2011): 5 [2] Seger et al. Animal derived surfactant extract for treatment of respiratory distress syndrome (2009): 10(1474) [3] Howlett et al. Inositol for respiratory distress syndrome in preterm infants (2012): 3(355) [4] Soll et al. Prophylactic animal derived surfactant extract for preventing morbidity and mortality in preterm infants (1997): 8 [5] Soll et al. Prophylactic protein free synthetic surfactant for preventing morbidity and mortality in preterm infants (2010): 7
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-30
porcine lung phospholipid fraction, poractant alfa, in the United Kingdom in 2012. 101
Reimbursement prices for other European countries can be found in Annex 6.23.1.102 In order
to widen the availability of surfactant treatment, synthetic preparations need to be
developed that can be produced in large quantities and at a reasonable cost. Although some
effective synthetic surfactants have been developed, the development of the key
hydrophobic surfactant proteins involved in increased alveolar stability, SP-B and SP-C, are
too big to synthesize, structurally complex, or unstable in pure form.100 Development of
clinically active synthetic surfactants has turned out to be more complicated than initially
anticipated and further research and development need to be undertaken.
Table 6.23.6. The reimbursed price for animal derived surfactants in the United Kingdom
in 2012
Molecule List Pack £ per unit
Poractant alfa VIAL 80 MG 3 ML 547.40
Poractant alfa VIAL 80 MG 1.5 ML 281.64
Beractant VIAL 25 MG 8 ML 306.43
Source: National Health Service England and Wales: Electronic Drug Tariff 101
Figure 6.23.13. Comparison of pharmaceutical surfactant interventions and regimens in
reducing risk of neonatal mortality from RDS
0
0.2
0.4
0.6
0.8
1
1.2
multiple doses VS single doseof exogenous surfactant
natural surfactant VSsynthetic surfactant
protein containing syntehticsurfactant VS animal derived
surfactantmultiple doses VS single dose
of exogenous surfactant
Re
lati
ve R
isk
wit
h 9
5%
co
nfi
de
nce
inte
rval
Pharmaceutical Interventions for RDS OUTCOME: Neonatal mortality
Treatment Prophylaxis
Intervention
>1 =
fav
ors
co
ntr
ol
<1 =
fav
ors
tre
atm
ent
[#] Cochrane Review (year): trials (subjects) [1] Soll et al. Multiple versus single doses of exogenous surfactant for the prevention or treatment of neonatal respiratory distress syndrome (2009): 2 [2] Soll et al. Natural surfactant extract versus synthetic surfactant for neonatal respiratory distress syndrome (2001). [3] Pfister et al. Protein containing synthetic surfactant versus animal derived surfactant extract for the prevention and treatment of respiratory distress syndrome (2007): 2(1028) [4] Soll et al. Multiple versus single doses of exogenous surfactant for the prevention or treatment of neonatal respiratory distress syndrome (2009): 1
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-31
3. Research and Development
Neonatal conditions have multiple causes; therefore, solutions will not come through a
single discovery, but will depend on an array of discoveries addressing multiple biological,
clinical, and social-behavioral risk factors. The pipeline will need to address both the
prevention of neonatal conditions and the care and survival gap. This will involve different
approaches along the pipeline of innovation.
3.1 Pharmaceuticals
3.1.1 Preterm
The Global Action Report on Preterm Birth released by the WHO, emphasized descriptive
and discovery learning to better understand preventative methods to preterm birth in
various contexts while development and delivery research is emphasized for premature
baby care.3
Based on the United States National Institutes of Health, 498 clinical trials were found for
preterm and premature conditions in which 235 of them are open studies.103 In 2005, the
March of Dimes initiated the Prematurity Research Initiative which funds research into the
causes and treatments of prematurity.104 More than US$ 15 million have been awarded to 43
grantees over the past six years.104
Researchers are working to identify the causes of premature birth and new treatments to
prevent or halt preterm labor. A recent development shows promise, but only for a minority
of high-risk women with premature cervical shortening. Clinical trials suggest that
progestational agents (PA) may modify the signal transduction pathways that are involved
in cervical ripening. 105 Progestational agents seem to regulate pathways which prevent
preterm birth, specifically claudin proteins.105 However, how PAs helps prevent preterm
labor and which forms of progesterone may be most effective is still to be determined.104 It
should be noted that Makena® (17-alpha-hydroxyprogesterone caproate) was approved by
the FDA in the USA only in 2011 for women with a history of at least one previous
spontaneous preterm birth.41
Several factors are hypothesized to help regulate the timing of labor including the drop in
enzyme levels of caspase-3 triggering labor and the closing of SK3 (potassium) channels in
the cell membranes preventing potassium flow out of the uterine muscle cells.106,107 The
enzyme, caspase-3, may help prevent contractions until term when levels drop sharply
triggering labor. Prior to the onset of labor, active caspace-3 levels and fragmentation of the
uterine myocyte contractile proteins decline suggesting that uterine caspase-3 acts as an
anticontractile agent.108 If this is true, it may be possible to develop drugs to regulate enzyme
levels and prevent preterm labor. Additionally, the SK3 channels in cell membranes that
allow potassium to flow out of the uterine muscle cells are believed to relax the uterus,
allowing pregnancy to continue to term. These channels may close, prompting labor to
begin.106 If this proves correct, it could lead to the development of drugs that open the
channels to prevent or half preterm labor.
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-32
A simple approach that is being investigated is the administration of vitamin D supplements
for women with uterine infections. This may help prevent preterm labor by suppressing
inflammation.105
3.1.2 Sepsis
Based on the US National Institutes of Health, 96 clinical trials were found for neonatal
sepsis in which 38 of them are open studies.87
Many cases of neonatal sepsis never reach a health care facility and oral antibiotic therapy
must be considered where no health care providers trained to give parenteral antibiotics are
available.83 The incremental benefit of injectable over oral antibiotics is not clear, but oral
antibiotic therapy is certainly better than no antibiotic therapy at all.8 A series of trials are
evaluating the impact of home and clinic-based seven-day intramuscular and oral antibiotic
therapy for neonatal sepsis in low-income countries.83 The available data on the effect of oral
cotrimoxazole in community-based treatment of serious neonatal bacterial infections are
promising, but concerns of high resistance rates and side effects such as neonatal jaundice
have been reported.84
New, better absorbed oral antibiotics should be considered. Second-generation
cephalosporins (e.g. cefadroxil and cefuroxime) have shown excellent safety profile, a
spectrum of activity similar to cotrimoxazole, and may be more effective given the high
resistance of neonatal pathogens to cotrimoxazole.8 Ciprofloxacin is also becoming
increasingly accepted as safe for neonate use, but warrants further investigation for
treatment of infections in newborns.8 However, the current costs for these agents and the
potential for exacerbating antimicrobial resistance may limit widespread use.83 Newer
antibiotics that are effective when given orally, as well as the safety and efficacy of oral plus
injectable antibiotics were also identified as research priorities by technical experts to reduce
global newborn infection-related mortality by 2015.109
3.1.3 Birth Asphyxia
Based on the United States National Institutes of Health, 39 studies were found for birth
asphyxia in which 19 of them are open studies.110
One of the most common birth complications is RDS where babies struggle to breathe
because their immature lungs do not produce enough surfactant, a protein that keeps small
air sacs in the lungs from collapsing.111 Since the introduction of surfactant therapy in 1990,
deaths from RDS have been reduced by two-thirds.111 Despite these advancements, about 20%
of babies with RDS do not respond to surfactant treatment and further discovery and
development is needed.111 Natural surfactant contains four known proteins – SP-A, SP-B, SP-
C, and SP-D – but surfactant treatments only contain SP-B and SP-C.111 Research is being
conducted to study the structure and function of SP-B to improve the synthetic surfactant to
mimic the activity of the natural protein and be effective when the one currently available
fails.111, 112 Furthermore, a new generation of synthetic surfactants containing simplified
phospholipid mixtures and small amounts of peptides replacing the hydrophobic proteins is
currently under development and should be introduced into the market in the near future.100
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-33
In addition to surfactants, many newborns with RDS receive additional oxygen and
mechanical breathing assistance. However, these treatments can contribute to lung injury
and bronchopulmonary dysplasia.111 Research is being done to see whether adding SP-D to
commercial surfactant treatments can help the immune system fight off lung infections and
prevent the inflammation that contributes to lung injuries and bronchopulmonary
dysplasia.111, 113
Further research have been conducted in animals to test the effects of administration of
caffeine on metabolic variables with peripartum asphyxia. Findings suggest that
administering caffeine immediately after birth to neonatal pigs with severe oxygen
restriction resulted in significant improvements in metabolic variables such as triglyceride
and lactate concentrations.113
3.2 Diagnostics
3.2.1 Sepsis
Recent developments in microtechnologies, particularly microfluidics, have provided the
greatest contribution to the diagnosis of neonatal sepsis. This technology uses the unique
properties of continuous flow micro-volume channels to study the behavior, precise control,
and manipulation of fluids.8 When applied to bacterial DNA protein microarray
hybridization, DNA probes specific to selected targets that are spotted on a glass or silicon
slide in a known order.114 Target DNA fragments are labeled with a reporter molecule,
combined into a single hybrid, and measured using fluorescent signals to identify specific
sepsis pathogen such as bacterial meningitis, acute viral respiratory tract infections, and
neonatal sepsis.60,115 This method has also been used to detect antimicrobial resistance and
virulence genes in research settings.79
Microfluidic technology has also developed small, disposable, single-use diagnostic
cartridges or cards that have been called “lab-on-a-chip” (LOC).115 Some LOCs have
combined sample preparation, biomarkers, real-time PCR, and DNA microarrays to
determine indices of inflammation, pathogen identification, and antimicrobial susceptibility
patterns at the point of care115, 116 Its performance for sensitivity, specificity, and
reproducibility levels are comparable to those of central laboratory analyzers and requires
little user input other than the insertion of the sample.8 Samples as little as a single drop of
blood, faeces, and saliva have been tested with encouraging results.8 Currently, LOCs are
being evaluated for use in sepsis and are not yet in clinical use nor are they licensed by
regulatory authorities.8
3.3 EC Framework Programme
There have been 13 projects on research and development for neonatal conditions funded by
the EC Framework Programme since 2004.117,118, 119 One project was funded by the Sixth EC
Framework Programme (FP6) and 12 projects by the Seventh EC Framework Programme
(FP7). The complete list of projects funded by the EC Framework Programme since 2004 is
listed below sorted by each neonatal condition. Starred projects indicate an overlap between
neonatal conditions and are listed in all relevant categories.
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-34
Preterm (11 projects total)117:
Treatment (8 projects)
New approach to treatment of the blinding disease retinopathy of prematurity (ROP)
(FP7)
Efficacy and safety of inhale budesonide in very preterm infants at risk for
bronchopulmonary dysplasia (FP7)
Management of hypotension in the preterm extremely low gestational age newborn
(FP7)
Evaluation of antibiotics (ciprofloxacin and fluconazole) for the treatment of
infections in preterm and term neonates (FP7)*
No pain during infancy by adapting off-patent medicines (FP7)
Documentation of lung growth after tracheal occlusion to reverse pulmonary
hypoplasia in congenital diaphragmatic hernia. Experimental studies in the rat and
clinical implications of fetal therapy (FP7)
Treat Infections in Neonates 2 – Evaluation of an infective agent (azithromycin) for
the treatment of infections in preterm and term neonates (FP7)*
Does vascular endothelial growth factor gene therapy safely improve outcome in
severe early-onset fetal growth restriction? (FP7)
Diagnostics (2 projects)
Brain diagnostics and monitoring in early neonatal period (BraDiMo) (FP7)
Special non-invasive advances in foetal and neonatal evaluation network (FP6)
Basic science and other fields of research (1 project)
Effective perinatal intensive care in Europe: translating knowledge into evidence
based practice (FP7)
Sepsis (4 projects total)118:
Treatment (3 projects)
European multicenter network to evaluate pharmacokinetics, safety and efficacy of
meropenem in neonatal sepsis and meningitis (FP7)
Evaluation of antibiotics (ciprofloxacin and fluconazole) for the treatment of
infections in preterm and term neonates (FP7)*
Treat infections in NeoNates 2 – Evaluation of an infective agent (azithromycin) for
the treatment of infections in preterm and term neonates (FP7)*
Diagnostics (1 project)
Fast automated multiplex analysis of neonatal sepsis markers on a centrifugal
microfluidic platform (FP7)
Birth Asphyxia (0 projects total)119
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-35
4. Existing Resource Flows
4.1 Finance for Research and Development
Global spending on maternal, newborn, and child health (MNCH) has been increasing from
US$ 2.1 billion in 2003 to almost US$ 3.5 billion in 2006, with child health accounting for
more than two-thirds of total aid to MNCH. 120 In 2006, the two leading contributors
supporting MNCH were the United States government and the World Bank, which
collectively contributed US$ 1.4 billion.89 Although donor funding has increased for maternal,
newborn, and child health, no analysis to date has disaggregated aid specifically for
newborns.121
Based on the analysis of donor-reported data, donor attention to newborn survival has
increased since 2002, but does not appropriately reflect the aid needed with over three
million newborn deaths each year.121 For low- and middle-income countries (LMIC), where
the majority of total neonatal deaths occur, the investment in research funding for neonatal
survival is extremely low. It is estimated that only around US$ 20 million per year is invested
into research for neonatal survival.122 Defining specific funding allocations for research on
neonatal conditions is not possible in current research resource reporting for either high- or
low-income countries.120 The low investment suggests a large potential for public-private
partnership (PPP) collaborations. Identifying incentives to foster research funding is
recommended and necessary (See Chapter 8).
Currently, none of the neonatal conditions – preterm birth, neonatal sepsis, and birth
asphyxia – are listed as one of the diseases on G-FINDER.123 Donors interested in funding
research and development for neonatal conditions need to be able to make substantial
investment decisions based on accurate data regarding funding flows, gaps, and
duplications. The inclusion of neonatal conditions on funding surveys such as G-FINDER
can provide funders with better information and hopefully stimulate increased efficiency
and investment to improve neonatal health.
According to a recent 2012 UN commission report on life-saving commodities for women
and children, an investment of US$ 2.6 billion over five years to scale up 13 key commodities
would cumulatively save over six million women and children.89 The list includes a
preliminary sample of overlooked life-saving commodities that represent common
challenges and require a priority response, but are not exhaustive.89 Of the 13 recommended
commodities, four of them focus on interventions for newborn conditions that can have a
large potential impact (Table 6.23.7).
Within the European Union, following the requirements of the Paediatric Regulation, the
EMA produces a yearly updated "priority list" of medicines in need for children. 124 , 125
Neonates are included in these pan-European efforts. These Paediatric Regulations require
that any new drug, whatever its main target, should also be considered for potential
paediatric use which forces all pharma companies to think strategically in terms of paediatric
medicines.
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-36
Table 6.23.7. Newborn health commodities recommended in the 2012 Commissioners’
Report
Newborn health commodity Examples of key barriers Potential 5-year impact
Injectable antibiotics –
neonatal sepsis
Poor compliance by health
workers
1.22 million neonatal lives
saved
Antenatal corticosteroids –
preterm RDS
Low awareness of product
impact 466 000 neonatal lives saved
Chlorhexidine – newborn
cord care
Limited awareness and
demand 422 000 neonatal lives saved
Resuscitation devices –
newborn asphyxia
Requires trained health
workers 336 000 neonatal lives saved
Source: Every Woman Every Child. UN Commision on Life-Saving Commodities for Women and
Children: Commissioners’ Report September 2012; 2012 Sept. 89
Despite the large global burden from neonatal conditions, a recent global analysis suggests
that newborn survival will remain vulnerable on the global agenda without adequate
funding and without high-level engagement of policy-makers.3 For this reason, it becomes
imperative that more funding is allocated towards research and development addressing
neonatal conditions.
5. Challenges and Research Opportunities
Although the overall under-five mortality has been declining, neonatal mortality are
lagging in improvements and is becoming a larger contributor in the under-five deaths
The latest data in 2011 indicate that neonatal deaths account for 43% of under-five
deaths worldwide. The highest share (55%) of neonatal deaths for under-five deaths is
seen in developed regions
Each neonatal condition has numerous confirmed and hypothesized etiology and
contributing risk factors which makes addressing these conditions complex
Pharmaceutical gap which presently exist offer research opportunities:
Preterm Birth:
o Development of a more simplified dosing regimen and single dose packaging
of tocolytics to prevent or delay premature labour.
o Development of tocolytics with side-effects in mothers and newborns.
o Evidence-based protocols for use of injectable antenatal corticosteroids to
prevent respiratory distress syndrome.
o Clearly labeled, pre-packaged or pre-filled delivery systems of antenatal
corticosteroid products.
Sepsis:
o Rapid diagnostics for neonatal sepsis to prevent late or inadequate
administration of necessary antibiotics.
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-37
o Appropriate product formulation and packaging for treating neonatal sepsis,
especially low-dose injectable gentamicin.
o Development of shorter course antibiotics, oral antibiotics, and antibiotics
with fewer side effects for newborns.
o Development of diagnostic tools for neonatal conditions, which can help
reduce the inappropriate use of antibiotics.
o Development of new and effective antibiotics to treat bacterial infections that
are or will soon become resistant to current antibiotics (see Chapter 6.1).
Birth asphyxia:
o Development of effective and lower-cost synthetic surfactants
o Development of a more stable oral surfactant
Many of the current treatment regimens require properly trained care providers to
administer these technologies. The best methods to train these providers need to be
researched.
6. Conclusions
Neonatal conditions need to be prioritized to achieve MDG 4. Addressing neonatal
conditions can have a major impact in reducing the global burden of disease as these
conditions have the most effect on potential for years lived with disability (YLD) and years of
life lost (YLL). Although the burden of disease is largest in developing countries, neonatal
conditions are of a global concern as the share of neonatal deaths in under-five deaths are
highest in developed countries.
Further research and development for rapid diagnostic tools and appropriate treatments
should be prioritized. Simple product innovations such as fixed-dose technology for simple
treatment administration can increase treatment usage in lower-resource settings, as well as
the need for continuous innovation in developing new effective antibiotics to treat infections
resistant to current antibiotics. A large challenge also remains that most of the current
research and development are focused on treatments and not on prevention, in part due to
the lack of understanding of the multiple etiology for each of these neonatal conditions.
Furthermore, most published research has been conducted in high-income countries and
research in developing, delivering, and testing community-based interventions in lower-
resource settings are needed.
Research and development of new or more affordable pharmaceuticals, such as synthetic
surfactants, to address neonatal conditions require substantive investment and long-term
support. Increased support from the European Commission is imperative to reduce the
burden of neonatal conditions such as preterm birth, neonatal sepsis, and birth asphyxia in
Europe and the world.
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-38
References
1 WHO. The global burden of disease: 2004 update. Geneva: World Health Organization; 2008.
2 Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional mortality
from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global
Burden of Disease Study 2010. The Lancet. 2012 Dec;380(9859):2095–128.
3 March of Dimes, PMNCH, Save the Children, WHO. Born Too Soon: The Global Action Report on
Preterm Birth. Geneva: World Health Organization; 2012.
4 Liu L, Johnson HL, Cousens S, Perin J, Scott S, Law JE, Rudan I, Campbell H, Cibulkis R, Li M,
Mathers C, Black RE. Global, regional, and national causes of child mortality: an updated systematic
analysis for 2010 with time trends since 2000. The Lancet. 2012. 379(9832): 2151 – 2161.
5 Rogers LK, Velten M. Maternal inflammation, growth retardation, and preterm birth: insights into
adult cardiovascular disease. Life Sci. 2011 Sep 26;89(13-14):417–21.
6 Lawn JE, Zupan J. 4 million neonatal deaths: when? Where? Why? 2005 [cited 2013 Jan 20]; Available
from: http://www.unasus-ufpel.net/dspace/handle/123456789/209
7 Neonatal sepsis - PubMed Health [Internet]. [cited 2013 Jan 21]. Available from:
http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0004557/
8 Edmond K, Zaidi A. New Approaches to Preventing, Diagnosing, and Treating Neonatal Sepsis.
PLoS Medicine 2010; 7(3)
9 WHO | Neonatal sepsis - a major killer to be tackled in communities [Internet]. [cited 2013 Jan 21].
Available from:
http://www.who.int/maternal_child_adolescent/news_events/news/2009/19_01/en/index.html
10 Lawn JE, Manandhar A, Haws RA, Darmstadt GL. Reducing one million child deaths from birth
asphyxia – a survey of health systems gaps and priorities. Health Research Policy and Systems.
2007;5(1):4.
11 Neonatal Handbook [Internet]. [cited 2013 Jan 21]. Available from:
http://www.netsvic.org.au/nets/handbook/index.cfm?doc_id=11236
12 Zupan J, Aahman E. Perinatal mortality for the year 2000: estimates developed by WHO. Geneva:
World Health Organization, 2005.
13 UNICEF, WHO, World Bank, UN Population Division. Level and trends in child mortality. Geneva:
United Nations Children’s Fund; 2012.
14 Martines J, Paul VK, Bhutta ZA, Koblinsky M, Soucat A, et al. Neonatal survival : a call for action.
The Lancet, 2005, 365(9465): 1189 – 1197.
15 Lawn JE, Knney M, Black RE, Pitt CP, Cousens S, et al. A decade of change for newborn survival,
policy and programmes: a multi-country analysis. Health Policy and Planning, 2012, in press.
16 Global Burden of Disease Study 2010 (GBD 2010) Results by Cause 1990-2010 | Institute for Health
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-39
Metrics and Evaluation [Internet]. [cited 2013 Jan 20]. Available from:
http://www.healthmetricsandevaluation.org/ghdx/record/global-burden-disease-study-2010-gbd-
2010-results-cause-1990-2010
17 Facts and figures [Internet]. [cited 2013 Jan 21]. Available from: http://www.euro.who.int/en/what-
we-do/health-topics/Life-stages/maternal-and-newborn-health/facts-and-figures
18 Siegrist CA. Mechanisms by which maternal antibodies influence infant vaccine responses: review
of hypotheses and definition of main determinants. Vaccine, 2003, 21: 3406-3412.
19 Levy O. Innate immunity of the newborn: basic mechanisms and clinical correlates. Nat Rev
Immunol, 2007, 7: 379-390.
20 Poehling KA, Thomas TR, Griffin MR, Craig AS, Whitney CG, Zell E, Lexau CA, Thomas AR,
Harrison LH, Reingold AL, Hadler JL, Farley MM, Anderson BJ, Schaffner W. Invasive
Pneumococcal Disease Among Infants Before and After Introduction of Pneumococcal Conjugate
Vaccine. JAMA, 2006, 295(14): 1668-1674.
21 Beck S, Wojdyla D, Say L, Betran AP, Merialdi M, Requejo JH, Rubens C, Menon R, Van Look PF.
The worldwide incidence of preterm birth: a systematic review of maternal mortality and morbidity.
22 Sinha A, Lieu TA, Paoletti LC, Weinstein MC, Platt R. The projected health benefits of maternal
group B streptococcal vaccination in the era of chemoprophylaxis. Vaccine, 2005, 23: 3187-3195.
23 Quiambao BP, Nohynck H, Kayhty H, Ollgren J, Gozum L, et al. Maternal immunization with
pneumococcal polysaccharide vaccine in the Philippines. Vaccine, 2003, 21: 3451-3454.
24 Safety and Immunogenicity of a Group B Streptococcus Vaccine in Non Pregnant and Pregnant
Women 18-40 Years of Age [Internet]. [cited 2013 Mar 14]. Available from:
http://clinicaltrials.gov/ct2/show/study/NCT01193920
25 Conde-Agudelo A, Rosas-Bermadez A, Kafury-Goeta AC. Birth spacing and risk of adverse
perinatal outcomes. JAMA, 2006, 295(15): 1809-1823.
26 Tsui AO, McDonald-Mosley R, Burke AE. Family planning and the burden of unintended
pregnancies. Epidemiologic reviews, 2010, 32: 152 – 174.
27 McDonald SD, Han Z, Mulla S, Beyene J. Overweight and obesity in mothers and risk of preterm
birth and low birthweight infants: systematic review and meta-analyses. British Medical Journal,
2010, 341.
28 Honein MA, Kirby RS, Meyer RE, Xing J, Skerrette NI, et al. The association between major birth
defects and preterm birth. Maternal and Child Health Journal, 2009, 13: 164 – 175.
29 Christianson A, Howson C, Modell B. March of Dimes Global Report on Birth Defects: the hidden
toll of dying and disabled children, 2006. New York: March of Dimes Birth Defects Foundation.
30 Goldenberg RL, Culane JF, Iams J, Romero R. Epidemiology and causes of preterm birth. The Lancet,
2008, 371: 73 – 82.
31 Austin MP, Leader L. Maternal stress and obstetric and infant outcomes: epidemiological findings
and neuroendocrine mechanisms. Australian and New Zealand Journal of Obstetrics and
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-40
Gynaecology, 2000, 40: 331 – 337.
32 Coker AL, Sanderson M, Dong B. Partner violence during pregnancy and risk of adverse pregnancy
outcomes. Paediatric and perinatal epidemiology, 2004, 18(4): 260 – 269.
33 Challis JR, Smith SK. Fetal endocrine signals and preterm labor. Biology of the Neonate, 2001, 79(3-
4): 163 – 167.
34 Wadhwa PD, Culhane JF, Rauh V, Barve SS. Stress and preterm birth: neuroendocrine,
immune/inflammatory, and vascular mechanisms. Maternal and Child Health Journal, 2001, 5: 119 –
125.
35 Schoenborn CA, Horm J. Negative moods as correlates of smoking and heavier drinking:
implications for health promotion. Advance Data, 1993, 1.
36 Donders GG, Desmyter J, De Wet DH, Van Assche FA. The association of gonorrhea and syphilis
with premature birth and low birthweight. Genitourinary medicine, 1993, 69: 98 – 101.
37 Bhutta ZA, Dean SV, Imam AM, Lassi ZS. 2011a. A Systematic Review of Preconception Risks and
Interventions. Karachi. The Aga Khan University.
38 Kamali A, Quigley M, Nakiyingi J, Kinsman J, Kengeya-Kayondo, J, et al. Syndromic management
of sexually-transmitted infections and behavior change interventions on transmission of HIV-1 in
rural Uganda: a community randomized trial. The Lancet, 2003, 361: 645 – 652.
39 Andrew RL, Day MC. Perinatal complications associated with maternal tobacco use. Seminars in
Neonatology, 2000, 5(3): 231 – 241.
40 Elsinga J, De Jong-Potjer LC, Van Der Pal-De Bruin KM, Le Cessie S, Assendelft W, et al. The effect
of preconception counseling on lifestyle and other behavior before and during pregnancy. Women’s
health Issues, 2008, 18: S117 – 125.
41 FDA Statement on Makena. [Internet]. [cited 2013 Mar 15]. Available from:
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm279098.htm
42 Meis PJ, Klebanoff M, Thom E, Dombrowski MP, Sibai B, Moawad AH, Spong CY, Hauth JC,
Miodovnik M, Varner MW, Leveno KJ, Caritis Sn, Iams JD, Wapner RJ, Conway D, O’Sullivan MJ,
Carpenter M, Mercer B, Ramin SM, Thorp JM, Peaceman AM. Prevention of Recurrent Preterm
Delivery by 17 Alpha-Hydroxyprogesterone Caproate. The New England Journal of Medicine, 2003,
348(24): 2379 – 2385.
43 Sepsis [Internet]. [cited 2013 Jan 21]. Available from:
http://kidshealth.org/parent/pregnancy_center/newborn_health_conditions/sepsis.html#
44 McClure EM, Goldenberg RL, Brandes N, Darmstadt GL, Wright LL, et al. The use of chlorhexidine
to reduce maternal and neonatal mortality and morbidity in low-resource settings. Int J Gynaecol
Obstet, 2007, 97: 89-94.
45 Early-onset and late-onset neonatal group B streptococcal disease-United States, 1996-2004. MMWR
Morb Mortal Wkly Rep, 2005, 54: 1205-1208.
46 Bhutta ZA, Darmstadt GL, Hasan BS, Haws RA. Community-based interventions for improving
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-41
perinatal and neonatal health outcomes in developing countries: a review of the evidence. Pediatrics,
2005, 115: 519-617.
47 Rhee V, Mullany LC, Khatry SK, Katz J, LeClerq SC, et al. Maternal and birth attendant hand
washing and neonatal mortality in southern Nepal. Arch Pediatr Adolesc Med, 2008, 162:603-608.
48 Mullany LC, Darmstadt GL, Tielsch JM. Safety and impact of chlorhexidine antisepsis interventions
for improving neonatal health in developing countries. Pediatr Infect Dis J, 2006, 25: 665-675
49 Darmstadt GL, Saha Sk, Ahmed AS, Chowdhury MA, Law PA, et al. Effect of topical treatment with
skin barrier-enhancing emollients on nosocomial infections in preterm infants in Bangladesh: a
randomized controlled trial. Lancet, 2005, 1039-1045.
50 Edmond KM, Yandoh C, Quiglez MA, Amenga-Etego, S, Owusu-Agyei S, et al. Delayed
breastfeeding initiation increases risk of neonatal mortality. Pediatrics, 2006, 117: e380-386.
51 Edmond KM, Kirkwood BR, Amenga-Etego S, Owusu-Agyei S, Hurt LS. Effect of early infant
feeding practices on infection-specific neonatal mortality: an investigation of the causal links with
observational data from rural Ghana. Am J Clin Nutr, 2007, 86: 1126-1131.
52 Mullany LC, Katz J, Li YM, Khatry SK, LeClerq SC, et al. Breast-feeding patterns, time to initiation,
and mortality risk among newborns in southern Nepal. J Nutr, 2008, 138: 599-603.
53 Darlow BA, Graham PJ. Vitamin A supplementation to prevent mortality and short and long-term
morbidity in very low birthweight infants. Cochrane Database of Systematic Reviews 2007, CD000501.
54 Gogia S, Sachdev HS. Neonatal vitamin A supplementation for prevention of mortality and
morbidity in infancy: systematic review of randomized controlled trials. BMJ, 2009, 338: b919.
55 English M, Ngama M, Mwalekwa L, Peshu N. Signs of illness in Kenyan infants aged less than 60
days. Bull World Health Organ, 2004, 82: 323-329.
56 Clinical signs that predict severe illness in children under age 2 months: a multicenter study. Lancet,
2008, 371: 135-142.
57 Neal PR, Kleiman MB, Reynolds JK, Allen SD, Lemons JA, et al. Volume of blood submitted for
culture from neonates. J Clin Microbiol, 1986, 24: 353-356.
58 Jordan JA, Durso MB. Comparison of 16S rRNA gene PCR and BACTEC 9240 for detection of
neonatal bacteremia. J Clin Microbiol, 2000, 38: 2574 – 2578.
59 Jordan JA, Durso MB. Real-time polymerase chain reaction for detecting bacterial DNA directly
from blood of neonates being evaluated for sepsis. J Mol Diagn, 2005, 7: 575 – 581.
60 Weile J, Knabbe C. Current applications and future trends of molecular diagnostics in clinical
bacteriology. Anal Bioanal Chem, 2009, 394: 731 – 742.
61 Peters RP, van Agtmael MA, Danner SA, Savelkoul PH, Vandenbroucke-Grauls CM. New
developments in the diagnosis of bloodstream infections. Lancet Infect Dis, 2004, 4 : 751-760.
62 Mackeen AD, Seibel-Seamon J, Grimes-Dennis J, Baxter JK, Berghella V. Tocolytics for preterm
premature rupture of membranes. Cochrane Database of Sstematic Reviews 2011, Issue 10. Art. No.:
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-42
CD007062. DOI: 10.1002/14651858. CD007062.pub2
63 King JF, Flenady V, Papatsonis D, Dekker G, Carbonne B. Calcium channel blockers for inhibiting
preterm labour. Cochrane Database of Systematic Reviews, 2003, Issue I. Art. No.: CD002255. DOI:
10.1002/14651858.CD002255
64 Hofmeyr GJ, Essilfie-Appiah G, Lawrie TA. Amnioinfusion for preterm premature rupture of
membranes. Cochrane Database of Systematic Reviews 2011, Issue 12. Art. No.: CD000942. DOI:
10.1002/14651858.CD000942.pub2.
65 King JF, Flenady V, Papatsonis D, Dekker G, Carbonne B. Calcium channel blockers for inhibiting
pretermlabour. Cochrane Database of Systematic Reviews 2003, Issue 1. Art. No.: CD002255. DOI:
10.1002/14651858.CD002255.
66 Mackeen AD, Seibel-Seamon J, Grimes-Dennis J, Baxter JK, Berghella V. Tocolytics for preterm
premature rupture of membranes. Cochrane Database of Systematic Reviews 2011, Issue 10.
Art.No.:CD007062.DOI: 10.1002/14651858.CD007062.pub2.
67 Haas DM, Caldwell DM, Kirkpatrick P, McIntosh JJ, Welton NJ. Tocolytic therapy for preterm
delivery: systematic review and network meta-analysis. BMJ, 2012, 345:e6226 doi: 10.1136/bmj.e6226
68 McDonald HM, Brocklehurst P, Gordon A. Antibiotics for treating bacterial vaginosis in pregnancy.
Cochrane Database of Systematic Reviews 2007, Issue 1. Art. No.: CD000262. DOI:
10.1002/14651858.CD000262.pub3.
69 Thinkhamrop J, Hofmeyr GJ, Adetoro O, Lumbiganon P. Prophylactic antibiotic administration
during second and third trimester in pregnancy for preventing infectious morbidity and mortality.
Cochrane Database of Systematic Reviews 2002, Issue 4. Art. No.: CD002250. DOI:
10.1002/14651858.CD002250.
70 King JF, Flenady V, Cole S, Thornton S. Cyclo-oxygenase (COX) inhibitors for treating preterm
labour. Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No.: CD001992. DOI:
10.1002/14651858.CD001992.pub2.
71 Papatsonis D, Flenady V, Liley H. Maintenance therapy with oxytocin antagonists for inhibiting
preterm birth after threatened preterm labour. Cochrane Database of Systematic Reviews 2009, Issue
1. Art. No.: CD005938. DOI: 10.1002/14651858.CD005938.pub2.
72 PMNCH. A Global Review of the Key Interventions Related to Reproductive, Maternal, Newborn
and Child Health (RMNCH). Geneva, Switzerland: The Partnership for Maternal, Newborn, & Child
Health; 2011.
73 Jones G, Steketee RW, Black RE, Bhutta ZA, Morris SS. How many child deaths can we prevent this
year? The Lancet, 2003, 362(9377): 65-71.
74 Magnesium sulfate for women at risk of preterm birth for neuroprotection of the fetus [Internet].
[cited 2013 Feb 5]. Available from:
http://apps.who.int/rhl/pregnancy_childbirth/complications/preterm_birth/cd004661_lumbiganonp_
com/en/index.html
75 March of Dimes – Preterm labor [Internet]. [cited 2013 Feb 6]. Available from:
http://www.marchofdimes.com/pregnancy/pretermlabor_drugs.html
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-43
76 Flenady V, King JF. Antibiotics for prelabour rupture of membranes at or near term. Cochrane
Database of Systematic Reviews 2002, Issue 3. Art. No.: CD001807. DOI: 10.1002/14651858.CD001807.
77 Roberts D, Dalziel SR. Antenatal corticosteroids for accelerating fetal lung maturation for women at
risk of preterm birth. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD004454. DOI:
10.1002/14651858.CD004454.pub2.
78 Hopkins L, Smaill FM. Antibiotic regimens for management of intraamniotic infection. Cochrane
Database of Systematic Reviews 2002, Issue 3. Art. No.: CD003254. DOI: 10.1002/14651858.CD003254.
79 Ohlsson A, Lacy J. Intravenous immunoglobulin for preventing infection in preterm and/or low
birth weight infants. Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD000361. DOI:
10.1002/14651858.CD000361.pub2.
80 Mtitimila EI, Cooke RWI. Antibiotic regimens for suspected early neonatal sepsis. Cochrane Database
of Systematic Reviews 2004, Issue 4. Art. No.: CD004495. DOI: 10.1002/14651858.CD004495.pub2.
81 Gordon A, JefferyHE. Antibiotic regimens for suspected late onset sepsis in newborn infants.
CochraneDatabase of Systematic Reviews 2005, Issue 3. Art. No.: CD004501. DOI:
10.1002/14651858.CD004501.pub2.
82 World Health Organization. Acute Respiratory Infections In Children: Case Management In Hospitals In
Developing Countries. Geneva: World Health Organization; 1990.
83 Darmstadt GL, Batra M, Zaidi AK. Parenteral antibiotics for the treatment of serious neonatal
bacterial infections in developing country settings. Pediatr Infect Dis J, 2009, 28:S37 – 42.
84 Thaver D, Ali SA, Zaidi AK. Antimicrobial resistance among neonatal pathogens in developing
countries. Pediatr Infect Dis J, 2009, 28: S19 – 21.
85 Zaidi AK, Huskins WC, Thaver D, Bhutta A, Abbas Z, et al. Hospital-acquired neonatal infections in
developing countries. Lancet, 2005, 365: 1175 – 1188.
86 Bang AT, Bang RA, Baitule SB, et al. Effect of home-based neonatal care and management of sepsis
on neonatal mortality; field trial in rural India. Lancet, 1999, 354: 1955 – 1961.
87 A service of the U.S. National Institutes of Health – Neonatal Sepsis [Internet]. [cited 2013 Feb 5].
Available from: http://clinicaltrials.gov/ct2/results?term=neonatal&cond=%22Sepsis%22&pg=1
88 Every Woman Every Child – Injectable Antibiotics for Newborn Sepsis [Internet]. [cited 2013 Feb 6].
Available from: http://www.everywomaneverychild.org/component/content/article/1-about/316-
injectable-antibiotics-for-newborn-sepsis--product-profile-
89 Every Woman Every Child. UN Commision on Life-Saving Commodities for Women and Children:
Commissioners’ Report September 2012; 2012 Sept.
90 Soll RF, McQueen MC. Respiratory Distress Syndrome. Sinclair J, Bracken M: Effective Care of the
Newborn. New York: Oxford University Press, 1992: 325 – 358. [: ISBN 0-19-261737-0]
91 Jobe AH. Pulmonary surfactant therapy. New England Journal of Medicine, 1993, 328: 861 – 868.
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-44
92 Soll R, Ozek E. Prophylactic protein free synthetic surfactant for preventing morbidity and mortality
in preterm infants. Cochrane Database of Systematic Reviews, 2010, Issue 1. [DOI: 10.1002/14651858.
CD001079.pub2]
93 Seger N, Soll R. Animal derived surfactant extract for treatment of respiratory distress syndrome.
Cochrane Database of Systematic Reviews, 2009, Issue 2. [DOI:10.1002/14651858. CD007836]
94 Howlett A, Ohlsson A, Plakkal N. Inositol for respiratory distress syndrome in preterm infants.
Cochrane Database of Systematic Reviews 2012, Issue 3. Art. No.: CD000366. DOI:
10.1002/14651858.CD000366.pub2.
95 Stewart A, Brion LP, Soll R. Diuretics for respiratory distress syndrome in preterm infants. Cochrane
Database of Systematic Reviews 2011, Issue 12. Art. No.: CD001454. DOI:
10.1002/14651858.CD001454.pub3.
96 Soll R, Blanco F. Natural surfactant extract versus synthetic surfactant for neonatal respiratory
distress syndrome. Cochrane Database of Systematic Reviews 2001, Issue 2. Art. No.: CD000144. DOI:
10.1002/14651858.CD000144.
97 Pfister RH, Soll R, Wiswell TE. Protein containing synthetic surfactant versus animal derived
surfactant extract for the prevention and treatment of respiratory distress syndrome. Cochrane
Database of Systematic Reviews 2007, Issue 4. Art.No.: CD006069.DOI:
10.1002/14651858.CD006069.pub3
98 Tooley WH, Clements JA, Muramatsu K, et al. Lung function in prematurely delivered rabbits
treated with a synthetic surfactant. American Review of Respiratory Disease, 1987, 136: 651 – 656.
99 Soll R, Özek E. Multiple versus single doses of exogenous surfactant for the prevention or treatment
of neonatal respiratory distress syndrome. Cochrane Database of Systematic Reviews 2009, Issue 1. Art.
No.: CD000141. DOI:10.1002/14651858.CD000141.pub2.
100 Curstedt T, Johansson J. New synthetic surfactant–how and when? Neonatology. 2006;89(4):336–9.
101 National Health Service England and Wales: Electronic Drug Tariff [Internet]. [cited 14 February
2013]. Available from: http://www.ppa.org.uk/edt/February_2013/mindex.htm
102 Pharma Price Information (PPI) service. Gesundheit Österreich GmbH (Austrian Health Institute);
20123. Available from: www.goeg.at/en/PPI.
103 A service of the U.S. National Institutes of Health – Preterm AND Premature [Internet]. [cited 2013
Feb 5]. Available from:
http://clinicaltrials.gov/ct2/results?term=%22preterm%22+AND+%22premature%22
104 March of Dimes – Prematurity Research [Internet]. [cited 2013 Feb 6]. Available from:
http://www.marchofdimes.com/research/prematurityresearch.html#
105 Xu H, Gonzalez JM, Ofori E, Elovitz MA. Preventing cervical ripening: the primary mechanism by
which progestational agents prevent preterm birth? American journal of obstetrics and gynecology.
2008;198(3):314–e1.
106 Pierce S. The role and regulation of small conductance CA2 activated K channel subtype 3 in
myometrial contraction and placental development. Theses and Dissertations [Internet]. 2010 Jan 1;
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-45
Available from: http://ir.uiowa.edu/etd/1059
107 Pierce SL, England SK. SK3 channel expression during pregnancy is regulated through estrogen
and Sp factor-mediated transcriptional control of the KCNN3 gene. Am J Physiol Endocrinol Metab.
2010 Oct 1;299(4):E640–E646.
108 Jeyasuria P, Wetzel J, Bradley M, Subedi K, Condon JC. Progesterone-Regulated Caspase 3 Action
in the Mouse May Play a Role in Uterine Quiescence During Pregnancy Through Fragmentation of
Uterine Myocyte Contractile Proteins. Biol Reprod. 2009 May 1;80(5):928–34.
109 Bahl R, Martines J, Ali N, Bhan MK, Carlo W, Chan KY, et al. Research Priorities to Reduce Global
Mortality From Newborn Infections by 2015. The Pediatric Infectious Disease Journal, 2009, 28(1):
S43 – 48.
110 A service of the U.S. National Institutes of Health – Birth Asphyxia [Internet]. [cited 2013 Feb 6].
Available from: http://clinicaltrials.gov/ct2/results?term=birth+asphyxia
111 March of Dimes – Improving the treatment of premature babies [Internet]. [cited 2013 Feb 6].
Available from: http://www.marchofdimes.com/research/prematurity_treatment.html
112 University of Chicago – Department of Chemistry, Ka Yee C. Lee [Internet]. [cited 2013 Feb 6].
Available from: http://chemistry.uchicago.edu/faculty/faculty/person/member/ka-yee-c-lee.html
113 Sato A, Whitsett JA, Scheule RK, Ikegami M. Surfactant Protein-D Inhibits Lung Inflammation
Caused by Ventilation in Premature Newborn Lambs. American Journal of Respiratory and Critical
Care Medicine, 2010, 181(10): 1098 – 1105.
114 Zhang Y, Ozdemir P. Microfluidic DNA amplification – a review. Anal Chim Acta, 2009, 638: 115 –
125.
115 Yager P, Edwards T, Fu E, Helton K, Nelson K, et al. Microfluidic diagnostic technologies for global
public health, 2006, Nature, 442: 412 – 418.
116 Stevens DY, Petri CR, Osborn JL, Spicar-Mihalic P, McKenzie KG, et al. Enabling a microfluidic
immunoassay for the developing world by integration of on-card dry reagent storage. Lab Chip,
2008, 8: 2038 – 2045.
117 CORDIS simple search – Preterm [Internet]. [cited 14 February 2013]. Available
from:http://cordis.europa.eu/search/index.cfm?fuseaction=search.resultlist#page=1@perPage=10@q=
A5BBFD03420D2B259371C21DFB6F7902@type=sim@showtype=proj@sortBy=RELEVANCE@sortOrd
er=DESC
118 CORDIS simple search – Neonatal AND Sepsis [Internet]. [cited 14 February 2013]. Available from:
http://cordis.europa.eu/search/index.cfm?fuseaction=search.resultlist&#page=1@perPage=10@q=BE6
4DEBEBEBF762E58618BADDF4E67F7@type=hom@showtype=proj@sortBy=RELEVANCE@sortOrder
=DESC
119 CORDIS simple search – birth AND asphyxia [Internet]. [cited 14 February 2013]. Available from:
http://cordis.europa.eu/search/index.cfm?fuseaction=search.resultlist&#page=1@perPage=10@q=8132
D5B7B8E1BF806639634C9B92A08E@type=hom@showtype=result@sortBy=RELEVANCE@sortOrder=
DESC
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-46
120 Progress Towards Maternal, Newborn, and Child Health – The Living Proof Project [Internet].
[cited 2013 Feb 5]. Available from:
http://www.gatesfoundation.org/livingproofproject/Documents/progress-towards-maternal-
newborn-child-health.pdf
121 Pitt C, Lawn JE, Ranganathan M, Mills A, Hanson K. Donor Funding for Newborn Survival : An
Analysis of Donor-Reported Data, 2002-2010. PLoS Med 9(10): e1001332.
Doi:10.1371/journal.pmed.1001332
122 Lawn JE, Bahl R, Bergstrom S, Bhutta ZA, Darmstadt GL, Ellis M, et al. Setting Research Priorities to
Reduce Almost One Million Deaths from Birth Asphyxia by 2015. PLoS Medicine, 2011, 8(1):
e1000389
123 G-Finder: R&D Matrix [Internet]. [cited 15 February 2013]. Available from : g-
finder.policycures.org/gfinder_report/registered/docs/G-
FINDER_R&D%20Matrix_updated_2011.pdf
124 European Medicines Agency Pediatric regulation 26 January 2007 available at
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listin
g_000068.jsp
125 European Medicines Agency Revised priority list for studies into off-patent paediatric medicinal
products for the 7th Call of the Seventh Framework Programme (FP7) of the European Commission
(Work Programme 2013, to be published in July 2012)13 January 2012 EMA/98717/2012 Rev. 2012
Human Medicines Development and Evaluation
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-47
Annex
Annex 6.23.1: The reimbursed price for animal derived surfactants in European countries in 2012
Source: Pharma Price Information (PPI) service. Gesundheit Österreich GmbH (Austrian Health Institute); 20123. Available from: www.goeg.at/en/PPI
Country Product name Package Dosage
form
ATC Route of
admin.
Inn. &
Strength
No. of
units
Manufactu
rer
price/unit
Wholesale
price/unit
Net retail
price/unit
Gross
retail
price/unit Italy curosurf 1fl 3 ml 80
mg/ml
intratracheal
suspension
R07AA02 inhalation natural
phospholipids
240 mg
1 775.760000 € - 955.970000 € 1280.320000 €
Italy curosurf 2fl 1.5 ml 80
mg/ml
intratracheal
suspension
R07AA02 inhalation natural
phospholipids
120 mg
2 387.880000 € - 581.965000 € 640.160000 €
Spain curosurf 120 ; 1 vial
1.5 ml
1 intratracheal
suspension
R07AA02 inhalation natural
phospholipids
120 mg
1 259.560000 € - 310.470000 € 322.890000 €
Belgium curosurf 120 mg 1.5 ml
suspension
pour
instillation x
80 mg/ml
surfactant
pulmonaire
porcin en 1
récipient
unidose
endotracheop
ulmonary
instillation,
suspension
R07AA02 inhalation natural
phospholipids
120 mg
1 299.930000 € 304.790000 € - -
Greece curosurf 120 mg/1.5
ml btx1vialx1.5 ml
1 intratracheal
suspension
R07AA02 inhalation natural
phospholipids
120 mg
1 - 211.230000 € - 256.910000 €
United
Kingdom
curosurf 120 mg/1.5
ml
endotracheopulmon
ary suspension vials
(chiesi ltd) 1 vial
1x endotracheop
ulmonary
instillation,
suspension
R07AA02 inhalation natural
phospholipids
120 mg
1 - - UK**
328.634772 €
UK**
328.634772 €
Spain curosurf 240 ; 1 vial
3 ml
1 intratracheal
suspension
R07AA02 inhalation natural
phospholipids
1 480.180000 € - 531.090000 € 552.330000 €
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-48
240 mg
Belgium curosurf 240 mg 3 ml
suspension
pour
instillation x
80 mg/ml
surfactant
pulmonaire
porcin en 1
recipient
unidose
endotracheop
ulmonary
instillation,
suspension
R07AA02 inhalation natural
phospholipids
240 mg
1 419.600000 € 425.540000 € - -
United
Kingdom
curosurf 240 mg/3
ml
endotracheopulmon
ary suspension vials
(chiesi ltd) 1 vial
1x endotracheop
ulmonary
instillation,
suspension
R07AA02 inhalation natural
phospholipids
240 mg
1 - - UK**
638.739790 €
UK**
638.739790 €
Greece curosurf 240 mg/3
ml vial btx1vialx3
ml
1 intratracheal
suspension
R07AA02 inhalation natural
phospholipids
240 mg
1 - 413.300000 € - 472.110000 €
Denmark curosurf 80 mg/ml
endotra.pulm.inst.su
3 ml endotracheop
ulmonary
instillation,
suspension
R07AA02 inhalation natural
phospholipids
240 mg
1 - 1069.260049 € 1165.582405 € 1456.978007 €
Denmark curosurf 80 mg/ml
endotra.pulm.inst.su
1.5 ml endotracheop
ulmonary
instillation,
suspension
R07AA02 inhalation natural
phospholipids
120 mg
1 - 615.148835 € 671.507646 € 839.384558 €
Hungary curosurf 80 mg/ml
endotracheopulmon
ális csepegtető
szuszpenzió
1x3 ml
injekciós
üvegben
endotracheop
ulmonary
instillation,
suspension
R07AA02 inhalation natural
phospholipids
240 mg
1 410.031820 € 428.073220 € 431.460636 € 453.033154 €
Hungary curosurf 80 mg/ml
endotracheopulmon
ális csepegtető
szuszpenzió
2x1.5 ml
injekciós
üvegben
endotracheop
ulmonary
instillation,
suspension
R07AA02 inhalation natural
phospholipids
120 mg
2 218.101413 € 227.697882 € 229.392343 € 240.861190 €
Norway curosurf 80 mg/ml
endotrakeopulmona
l instillasjonsvæske.
suspensjon
1.5 ml endotracheop
ulmonary
instillation,
suspension
R07AA02 inhalation natural
phospholipids
120 mg
1 - 611.470680 € 639.745247 € 799.681559 €
Norway curosurf 80 mg/ml
endotrakeopulmona
l instillasjonsvæske.
suspensjon
1 x 3 ml endotracheop
ulmonary
instillation,
suspension
R07AA02 inhalation natural
phospholipids
120 mg
1 - 1222.942721 € 1275.669202 € 1594.586503 €
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-49
Norway curosurf 80 mg/ml
endotrakeopulmona
l instillasjonsvæske.
suspensjon
1 x 1.5 ml endotracheop
ulmonary
instillation,
suspension
R07AA02 inhalation natural
phospholipids
240 mg
1 - 611.470680 € 639.745247 € 799.681559 €
Norway curosurf 80 mg/ml
endotrakeopulmona
l instillasjonsvæske.
suspensjon
3 ml endotracheop
ulmonary
instillation,
suspension
R07AA02 inhalation natural
phospholipids
240 mg
1 - 1222.942721 € 1275.669202 € 1594.586503 €
Iceland curosurf 80 mg/ml
innöguf
1 hgl x 1.5 ml endotracheop
ulmonary
instillation,
suspension
R07AA02 inhalation natural
phospholipids
120 mg
1 - 547.987977 € 557.187278 € 699.270028 €
Iceland curosurf 80 mg/ml
innöguf
1 hgl x 3 ml endotracheop
ulmonary
instillation,
suspension
R07AA02 inhalation natural
phospholipids
240 mg
1 - 1020.451478 € 1029.653907 € 1292.215679 €
Slovenia curosurf 80 mg/ml
suspenzija za
endotraheopulmona
lno vkapavanje
škatla z 2
vialama z 1.5
ml suspenzije
endotracheop
ulmonary
instillation,
suspension
R07AA02 inhalation natural
phospholipids
120 mg
2 - 472.355000 € - -
Italy surfactal iv fl 50 ml 1 g solution for
infusion
R07AA parenteral ambroxol 1000
mg
1 - - 16.040000 € 17.640000 €
United
Kingdom
survanta 200 mg/8
ml
endotracheopulmon
ary suspension
bottles (abbvie ltd) 1
bottle
1 bottle intratracheal
suspension
R07AA02 inhalation natural
phospholipids
200 mg
1 - - UK**
357.561260 €
UK**
357.561260 €
Greece survanta 200 mg/8
ml vial btx1 vialx8
ml
1 intratracheal
suspension
R07AA02 inhalation natural
phospholipids
200 mg
1 - 304.420000 € - 356.160000 €
Spain survanta 25 mg/ml
suspension para
instilacion
endotraqueopulmon
ar . 1 vial de 8 ml
1 intratracheal
suspension
R07AA02 inhalation natural
phospholipids
200 mg
1 268.580000 € - 319.490000 € 332.270000 €
Hungary survanta
intratrachealis
szuszpenzió
1x8 ml
injekciós
üvegben
intratracheal
suspension
R07AA02 inhalation natural
phospholipids
200 mg
1 276.788586 € 288.967291 € 292.352961 € 306.969583 €
UK** This is the reimbursement price to community pharmacies for dispensing the medicine against a NHS prescription. For branded medicines, the price is the
NHS list price, set by the PPRS. For most generic medicines, this is the reimbursement price listed in Part VIII of the Drug Tariff. But where a supplier name is
specified on the prescription e.g. omeprazole AAH or a product is not listed in Part VIII, the pharmacist is reimbursed the supplier’s list price. The price includes
Update on 2004 Background Paper, BP 6.23 Neonatal Conditions
6.23-50
wholesaler and pharmacy margins that are not regulated. The United Kingdom does not hold information on the manufacturer or wholesale price. Community
pharmacies and hospitals may be able to purchase medicines at a discount to these prices. (United Kingdom)
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